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Title

Synthesis of N‑hydroxysuccinimide from succinicacid and hydroxylammonium chloride using
Amberlyst A21 as reusable solid base catalyst

Author(s)Le, Son Dinh; Nishimura, Shun; Ebitani, Kohki

Citation

AIP Conference Proceedings, 1929(1): 020017‑1‑
020017‑6

Issue Date

2018‑01‑22

Type

Conference Paper

Text version

publisher

URL

http://hdl.handle.net/10119/15747

RightsCopyright 2018 Authors. Published by AIP
Publishing. Son Dinh Le, Shun Nishimura and Kohki
Ebitani, AIP Conference Proceedings, 1929(1),20017 (2018) and may be found at
http://dx.doi.org/10.1063/1.5021930

Description

Japan Advanced Institute of Science and Technology

Synthesis of N-Hydroxysuccinimide from Succinic Acidand Hydroxylammonium Chloride using Amberlyst A21
as Reusable Solid Base Catalyst
Son Dinh Le1), Shun Nishimura1) and Kohki Ebitani1),*
1

Graduate School of Advanced Science and Technology,
Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa, 923-1292, Japan*Corresponding author: ebitani@jaist.ac.jp
Abstract. Solid base catalysts were studied for the first time to synthesize N-hydroxysuccinimide (NHS) through thereaction of succinic acid with hydroxylammonium chloride. The highest yield of 42% (±3%) with 65% (±4%)
selectivity toward NHS production was achieved by using Amberlyst A21, which is a weak base anion-exchange
resin. The present catalyst could be recycled during five runs without significant decreases in activity. Also, efficacy
for the Amberlyst A21 mediated reaction was also explored with other dicarboxylic acids such as phthalic acid,glutaric acid, and maleic acid.

Keywords. N-hydroxysuccinimide, succinic acid, hydroxylammonium chloride, solid base catalyst

INTRODUCTION
Cyclic N-hydroxyimides are versatile compounds
which are widely used in peptide synthesis [1], aerobic
oxidation [2-4], and polymerization [5, 6]. Particularly,
N-hydroxysuccinimide (NHS, Fig. 1) is a valuableintermediate in the formation of activated ester
derivatives for coupling reactions with amino acids,
peptides, or their esters [7].
Conventionally, cyclic N-hydroxyimide compounds
are prepared by the reaction of dicarboxylic anhydrides
with hydroxylammonium salt as a reagent. It is claimed FIGURE 1. Structure of N-hydroxysuccinimide (NHS).
that utilization of dicarboxylic acid form as a raw
material is not favorable regarding reaction kinetics [8] and its stability; i.e., it is quickly deactivated by the
acid-base reaction [9]. Therefore, seeking a process that employs dicarboxylic acids as a starting material
avoiding the step of converting them into corresponding dicarboxylic anhydrides is essential.
A U.S. patent disclosed a method to produce NHS in a good yield (95%) from succinic acid [10]. However,
the reaction system is complicated as it requires a Dean-Stark apparatus, a solvent capable of forming adehydration-condensation product with hydroxylamine and an azeotropic solvent. Furthermore, a stoichiometricamount of a deprotonating base was involved in treating with hydroxylammonium chloride, which causes theformation of salt waste during the synthesis. It is worth noting that using free hydroxylamine requires deliberate
manipulation due to its explosive nature. Therefore, hydroxylamine salts are generally employed. Another U.S.
patent reported a process to synthesize N-hydroxyphthalimide (NHPI, 86%) in water solvent without the

The Irago Conference 2017
AIP Conf. Proc. 1929, 020017-1–020017-6; https://doi.org/10.1063/1.5021930
Published by AIP Publishing. 978-0-7354-1621-5/$30.00

020017-1

addition of a base. This simple method, however, requires elevated temperature reaction (130 °C) and an
excessive amount of phthalic anhydride to hydroxylammonium phosphate (approx. 3 equiv) [9].
The use of solid base catalysts is continuously expanding because of its many advantages regarding
economic and environmental problems compared to that of liquid bases [11]. Along with the development insolid base catalysts, more recently, resin-bound catalysts have been becoming more and more important inorganic synthesis due to their recyclability, ease of separation and purification, and higher safety feature against
potential explosive reagents [12]. Many kinds of ion-exchange resins, namely Amberlyst, Amberlite, andDowex are now available at low cost, the greater diversity of functionalities, and higher loading capacities [13].
Amberlyst A21 is a weakly basic anion-exchange resin containing N(CH3)2 functional group and watermoisture (56-62%) [14-16], and its high catalytic activity, selectivity, and excellent stability for the Henry
reaction, Michael reaction, and transesterification reaction were explored [17-20]. Because the Amberlyst A21
possessed various important performances such as i) the less susceptibility to organic pollutants, ii) moreresistance to oxidation, hydrolysis and elevated temperature, and iii) excellent sorption capacity, and iv)
recyclability, it has also been applied for various applications in waste treatments such as removals of chromatesand azo dyes [21, 22].
Herein, to overcome the drawbacks from the previous methods on the NHS synthesis, this paper addresses
the production of NHS by carrying out a reaction between succinic acid and hydroxylammonium chloride in thepresence of catalytic amount of a solid base. Several catalysts and solvents were examined along with the
optimization of reaction conditions and other contributed factors (Scheme 1).

SCHEME 1. Synthesis of NHS with succinic acid and hydroxylammonium chloride over solid base catalyst.

EXPERIMENTAL
Chemicals
Succinic acid, potassium carbonate, magnesium oxide, acetonitrile, phenolphthalein, dimethyl sulfoxide(DMSO), acetic acid, and dimethylformamide (DMF) were supplied by Kanto Chemical Co., Inc. Phthalic acid,hydroxylammonium chloride, toluene, benzoic acid, 1,4-dioxane, N-hydroxysuccinimide, ethanol, and formic
acid were purchased from Wako Pure Chemical Ind. Ltd. Glutaric acid, Amberlyst A21, and Nhydroxyphthalimide were provided by Sigma Aldrich Japan. Amberlyst A26, Mg-Al hydrotalcite, and maleic
acid were obtained from Dow Chemical Co., Tomita Pharmaceutical Co. Ltd., and Tokyo Chemical Ind. Ltd.,
respectively.

Typical procedures for reaction, analysis, and recycling
The reaction was carried out in a 20-mL round-bottom flask with a reflux condenser. The flask was charged
with succinic acid (1 mmol), hydroxylammonium chloride (1.25 mmol), catalyst (0.5 g), and solvent (5 mL),and then the flask was immersed in an oil bath, which was held at 97 °C and 400 rpm. Heating was terminatedafter 8 hours and cooled to room temperature before analyzing.
For high-performance liquid chromatography (HPLC) analysis, formic acid (100 μL) was added into theanalyte as an internal standard, and then distilled water (16 mL) was added to dissolve the remaining reactants
and product. The obtained water phase (1 mL) was then withdrawn and diluted with water (10 mL) before
analyzing by HPLC (Column: Shodex RSpak DE-413L; Detector: RID-10A; Buffer solution: 10 mM H3PO4,
1.0 mL/min, 323 K). While, for proton nuclear magnetic resonance (1H-NMR), the analyte was dissolved in

020017-2

dimethyl sulfoxide-d6 (DMSO-d6) and analyzed by the Bruker Avance III, 400 MHz. Maleic acid (Purity =99%) was used as an internal standard in the case of 1H-NMR analysis.
To examine the recyclability of the solid catalyst, the used catalyst was recovered by simple filtration andwashed with water. After that, it was treated with 2% NH3 (2 mL) at room temperature in 1 h, followed bytreating with water (2 mL) in an oven at 80 °C for 1 h.

Isolation procedure
N-hydroxyphthalimide, which was obtained by the reaction of phthalic acid and hydroxylammonium
chloride, was isolated by crystallization method. After the reaction, toluene was removed by pipette filtration. A
minimum amount of hot distilled water was added to the reaction flask to dissolve the product. The catalyst wasthen separated by simple filtration, and the filtrate was cooled at room temperature. After 2 h crystallizing, all
the yellowish crystals formed were filtered and dried in vacuum to give the final product with the yield of 34%.

RESULTS AND DISCUSSION
To select an effective catalyst for the target reaction, several solid bases were compared their reactivities intoluene solvent. The results are summarized in Table 1. It is noticeable that among different kinds of catalysts,
only Amberlyst-types rein catalysts named as Amberlyst A21 and Amberlyst A26 showed activities to thereaction. In detail, the former catalyst could give the highest yield and selectivity of 42% (±3%) and 65%(±4%), respectively, while those of the latter are lower at 26% and 54% (entries 1 and 2). All the remaining
catalysts (MgO, Mg-Al hydrotalcites, and K2CO3) did not have any activity for the reaction (entries 3-6).
TABLE 1. Effect of catalyst[a]EntryCatalyst

Conv. /%

Yield /%

Sel. /%

1

Amberlyst A21

65

42

65

2

Amberlyst A26

48

26

54

3

MgO

0

0

0

4

Hydrotalcite (Mg/Al = 5.4)

0

0

0

5

Hydrotalcite (Mg/Al = 3.02)

0

0

0

6
K2CO3
0
0
0
[a] Reaction conditions: succinic acid (1 mmol), hydroxylammonium chloride (1.25 mmol), toluene (5 mL),reaction temperature (97 °C), reaction time (8 h), stirring speed (400 rpm).
The base amount of Amberlyst A21 is 0.1 mmol/g, which was measured by titration method using benzoic
acid (0.05 M) as a titrator and phenolphthalein (0.05 %wt.) as an indicator. Turn over number (TON) of thereaction was then calculated as described in Eq. 1. This TON value is over than 1, indicating that Amberlyst
A21 proceeded the synthesis of NHS, catalytically.

TON =Mole of desised product formed 0.42=
=8Base amount
0.05(EQUATION 1)

The catalyst amount was also optimized by varying it from 0 to 0.8 g of Amberlyst A21 (Table 2). It wasseen that without the catalyst, the reaction did not proceed at all (entry 1). Whereas, the yield of the productincreased along with the rise of catalyst amount from 0.1 g to 0.5 g (entries 2-4). Notably, the further addition
amount to 0.8 g of catalyst even had an adverse effect on the reaction as it made a significant decrease to 19 %in yield of NHS (entry 5).

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TABLE 2. Effect of amount of Amberlyst A21[a]EntryAmount /g

Base amount /mmol

Conv. /%

Yield /%

Sel. /%

1

0

0

0

0

0

2

0.1

0.01

13

9

69

3

0.3

0.03

49

33

67

4

0.5

0.05

65

42

65

5

0.8

0.08

54

19

35

[a] Reaction conditions: succinic acid (1 mmol), hydroxylammonium chloride (1.25 mmol), toluene (5 mL),reaction temperature (97 °C), reaction time (8 h), stirring speed (400 rpm).
The effect of solvents on the efficiency of the catalyst was then examined, and the results are shown in
Table 3. Among three kinds of solvents, which are classified by their polar properties, the non-polar solventswere the most suitable for the reaction (entries 1 and 2). The polar-protic and polar-aprotic solvents were lesseffective (entries 3, 4, 6) or failed to give the product (entries 5, 7, 8).
TABLE 3. Effect of solvents[a]EntrySolvent

Polarity

Conv. /%

Yield /%

Sel. /%

1

Toluene

65

42

65

2

1,4-dioxane

19

15

79

3

Water

10

3

30

4

Acetic acid

4

4

100

5

Ethanol

0

0

0

6

Acetonitrile

7

3

43

7

DMSO

0

0

0

Non-polar

Polar-protic

Polar-aprotic

8
DMF
0
0
0
[a] Reaction condition: succinic acid (1 mmol), hydroxylammonium chloride (1.25 mmol), Amberlyst A21(0.5 g), solvent (5 mL), reaction temperature (97 °C), reaction time (8 h), stirring speed (400 rpm).
To optimize the reaction time, a series of experiments were carried out, viz. 1h, 4 h, 8 h, 12 h and 24 h. Fig. 2
describes a considerable increase in yield as changing from 1h to 8h of reaction time. Keeping the reaction for amore extended period than 8 h, however, not only showed a modest increase in yield but also led to a drop in
selectivity.
Yield

Conv.

Sel.

80

80

70

70
Percentage /%Percentage /%

Conv.

60
50
40
30

Yield

Sel.

60
50
40
30

20

20

10

10
0

0
0

4

8

12

16

20

24

Time /h2
Cycle

FIGURE 2. Time course of the reaction

FIGURE 3. Catalyst recyclability

020017-4

Fresh

1

3

4

Finally, the catalyst was tested to evaluate its stability and recycling capabilities (Fig. 3). It was observedthat the catalyst could keep its efficiency for at least 5 runs without any significant loss in conversion andselectivity.
Having optimized the reaction parameters such as catalyst, catalyst amount, solvent, reaction time, theefficiency of the ideal protocol was tested for the reaction of other dicarboxylic acids such as phthalic acid,glutaric acid, and maleic acid. The results described in Table 4 showed that in case of phthalic acid, Nhydroxyphthalimide was also successfully synthesized and gave an isolated yield of 34% with high purity (entry
2). A low yield of only 6% was obtained in case of glutaric acid (entry 3), while the reaction with maleic acidwas failed to give the desired product (entry 4).
TABLE 4. Substrate scope[a]EntryDicarboxylic acid

Product

Yield /%

42[b]1Succinic acidN-hydroxysuccinimide

34[c]

2
Phthalic acidN-hydroxyphthalimide

6[d]3Glutaric acidN-hydroxyglutarimide

40
Maleic acidN-hydroxymaleimide[a] Reaction conditions: dicarboxylic acid (1 mmol), hydroxylammonium
chloride (1.25 mmol), Amberlyst A21 (0.5 g), toluene (5 mL), reaction
temperature (97 °C), reaction time (8 h), stirring speed (400 rpm).
[b] HPLC yield[c] Isolated yield, 24 h of reaction period, purity = 97%[d] NMR yield

CONCLUSION
In summary, Amberlyst A21 was found to be a potential recyclable solid base catalyst for the synthesis of Nhydroxysuccinimide from the reaction of succinic acid with hydroxylammonium chloride in toluene solvent.
The optimized conditions were applied for the reaction with other 3 dicarboxylic acids. However, only an
acceptable yield of N-hydroxyphthalimide was obtained from phthalic acid.

020017-5

ACKNOWLEDGEMENTS
S. D. Le gratefully acknowledges financial support from INOAC International Education and ScholarshipFoundation, master’s program scholarship from Japan Advanced Institute of Science and Technology, andMonbukagakusho Honor Scholarship from Japan Student Service Organization.
S. Nishimura would like to appreciate financial supports by JSPS-KAKENHI (No. 17H04966).

REFERENCES[1] G. H. L. Nefkens, G. I. Tesser and R. J. F. Nivard, Rec. Trav. Chim. Des Pays-Bas. 81, 683 (1962).
[2] Y. Ishii and S. Sakaguchi, Catal. Surv. Jpn 3, 27 (1999).
[3] Y. Ishii, S. Sakaguchi and T. Iwahama, Adv. Synth. Catal. 343, 393 (2001).
[4] R. A. Sheldon and I. W. C. E. Arends, Adv. Synth. Catal. 346, 1051 (2004).
[5] D. P. Vanderbilt and G. B. Butler, J. Macromol. Sci. Part A - Chem. 22, 541 (1985).
[6] K. Ahn, D. Koo and C. G. Willson, Polymer (Guildf) 36, 2621 (1995).
[7] G. W. Anderson, J. E. Zimmerman and F. M. Callahan, J. Am. Chem. Soc. 86, 1839 (1964).
[8] H. Jaensch, U.S. patent 2011/0319635 A1 (2011).
[9] F. Elke, U.S. patent 6,316,639 B1 (2001).
[10] Y. Kajikawa, U.S. patent 8,217,182 B2 (2012).
[11] Y. Ono and H. Hattori, in Solid Base Catalysis, edited by A. W. Castleman Jr and J. P. Toennies, K.
Yamanouchi, W. Zinth (Springer-Verlag Berlin Heidelberg, 2011).
[12] M. Bihani, P. P. Bora, G. Bez and H. Askari, Comptes Rendus Chim. 16, 419 (2013).
[13] M. Bihani, P. P. Bora, G. Bez and H. Askari, ACS Sustain. Chem. Eng. 1, 440 (2013).
[14] R. Ballini, L. Barboni and P. Filippone, Chem. Lett. 26, 475 (1997).
[15] M. Harada and T. Okada, J. Chromatogr. A 1085, 3 (2005).
[16] Moisture content in Amberlyst® A21 is available at the website of Sigma Aldrich, Japan:
http://www.sigmaaldrich.com/catalog/product/aldrich/216410?lang=ja&region=JP.
[17] R. Ballini, G. Bosica and P. Forconi, Tetrahedron 52, 1677 (1996).
[18] A. Palmieri, S. Gabrielli and R. Ballini, Chem. Commun. 46, 6165 (2010).
[19] F. Bonfils, I. Cazaux, P. Hodge and C. Caze, Org. Biomol. Chem. 4, 493 (2006).
[20] S. M. Dhuri and V. V Mahajani, J. Chem. Technol. Biotechnol. 81, 62 (2006).
[21] S. Mustafa, M. Khalid, A. Naeem, N. Rehana, and S. Murtaza, Environ. Technol. 23, 583 (2002).
[22] M. Greluk and Z. Hubicki, J. Hazard. Mater. 172, 289 (2009).

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