N -hydroxysuccinimide

Structural formula
General
Surname	N -hydroxysuccinimide
other names	1-hydroxy-2,5-pyrrolidinedione HOSu
Molecular formula	C 4 H 5 NO 3
Brief description	colorless and odorless crystalline solid
External identifiers / databases
CAS number 6066-82-6 EC number 228-001-3 ECHA InfoCard 100.025.456 PubChem 80170 Wikidata Q408833
properties
Molar mass	115.09 g mol −1
Physical state	firmly
Melting point	99-101 ° C
solubility	soluble in water
safety instructions
GHS labeling of hazardous substances no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

N -hydroxysuccinimide ( NHS , in structural formulas mostlyabbreviatedas HOSu , according to IUPAC 1-hydroxy-2,5-pyrrolidinedione ) is the N -hydroxy derivative of succinimide . The substance is mainly used in organic syntheses to produce so-called NHS esters .

presentation

N -hydroxysuccinimide is formed when succinic anhydride is reacted with hydroxylamine . After the methanol used as solvent has evaporated, the reaction takes place in the melt at 160 ° C. in vacuo. After the viscous residue has been extracted several times, the pure product is obtained in a 46% yield.

Instead of hydroxylamine, a simpler variant uses the easier-to-use hydroxylamine hydrochloride mixed with succinic anhydride, which is heated to 160 ° C in a rotary evaporator under vacuum until no more water escapes from the melt. After repeated extraction with several organic solvents, pure NHS is obtained in 44% yield.

Another simplification of the process is the reaction of hydroxylamine and succinic anhydride in water (presumably initially with the formation of monohydroxamic acid) and subsequent ring closure with elimination of water in vacuo at 105 ° C, which leads to the NHS monohydrate in 70-78% yield while avoiding costly extractions.

Heating the monohydrate for two hours under high vacuum to 80-90 ° C. gives pure anhydrous N-hydroxysuccinimide in quantitative yield.

properties

N -hydroxysuccinimide is a colorless and odorless crystalline solid. It is easily soluble in water and shows a weakly acidic reaction in it. NHS is a weak oxidizer . The heat of decomposition determined by DSC is −174 kJ · mol ⁻¹ or −1510 kJ · kg ⁻¹ .

use

In chemical and biochemical syntheses, N -hydroxysuccinimide is a versatile and frequently used compound.

By reacting with a carboxylic acid and an activating reagent , such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), NHS esters are produced therewith. NHS esters are “ activated carboxylic acids” and react easily with amino functions - for example of peptides or proteins - which are significantly more nucleophilic than alcohols .

NHS esters are relatively stable to hydrolysis.

Similar reagents for activating carboxylic acids are N -hydroxysulfosuccinimide sodium salt , 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT) and pentafluorophenol .

The oxidizing properties of NHS can be used for the ruthenium- catalyzed conversion of terminal alkynes into carboxylic acid derivatives.

The use of NHS to make active esters was first described in 1963 by George W. Anderson, Joan E. Zimmerman, and Francis M. Callahan.

toxicology

N -hydroxysuccinimide is neither carcinogenic nor teratogenic in the mouse and rat animal model . In the baker's yeast Saccharomyces cerevisiae , it does not trigger any mitotic gene changes .

literature

• B. Lygo: Handbook of Reagents for Organic Synthesis - Activating Agents and Protecting Groups. AJ Pearson and WR Roush (Eds.), Verlag Wiley, 1999, pp. 225-227.
• CA Montalbetti and V. Falque: Amide bond formation and peptide coupling. In: Tetrahedron 61, 2005, pp. 10827-10852, doi: 10.1016 / j.tet.2005.08.031 .
• VA Shibnev et al. a .: N-hydroxysuccinimide esters in the synthesis of collagen-type structures. In: Russian Chemical Bulletin 18, 1969, pp. 2367-2370, doi: 10.1007 / BF00906511 .

Individual evidence

1. ↑ ^{a b c d} Data sheet N-Hydroxysuccinimide (PDF) from Merck , accessed on December 25, 2019.
2. ^ Entry on succinimide. In: Römpp Online . Georg Thieme Verlag, accessed on December 28, 2014.
3. ↑ Patent US2816111 : Sulfonic acid derivatives. Registered on February 9, 1954 , published on December 10, 1957 , applicant: Farbenfabriken Bayer AG, inventor: R. Wegler, F. Grewe, K. Mehlhose. ‌
4. ↑ GW Anderson, JE Zimmerman, FM Callahan: The use of esters of N-hydroxysuccinimide in peptide synthesis . In: J. Am. Chem. Soc. tape 86 , no. 9 , 1964, pp. 1839–1842 , doi : 10.1021 / ja01063a037 .
5. ↑ Patent US5493031 : N-hydroxysuccinimide monohydrate. Filed June 16, 1994 , published February 20, 1996 , applicant: PPG Industries, Inc., inventor: C. Govindan. ‌
6. ↑ Grewer, T .; Klais, O .: Exothermic decomposition - investigations of the characteristic material properties , VDI-Verlag, series "Humanisierung des Arbeitsleben", Volume 84, Düsseldorf 1988, ISBN 3-18-400855-X , p. 9.
7. ↑ MA Gauthier u. a .: Synthesis of functional polymers by polymer-analogous reactions. In: Angew Chem 121, 2009, pp. 50-60, doi : 10.1002 / anie.200801951 .
8. ↑ E. Pedone et al. a .: An information rich biomedical polymer library. In: J Mater Chem 13, 2003, pp. 2825-2837. doi: 10.1039 / B306857A .
9. ↑ BM Trost u. a .: Ruthenium-catalyzed reactions - a treasure trove for atom-economical conversions. In: Angew Chem 117, 2005, pp. 6788-6825, doi: 10.1002 / ange.200500136 .
10. ↑ GW Anderson et al. a .: N-Hydroxysuccinimide Esters in Peptide Synthesis. In: JACS 85, 1963, p. 3039, doi: 10.1021 / ja00902a047 .
11. ↑ H. Dannenberg: N-hydroxy-succinimide, a non-carcinogenic N-hydroxy compound. In: Zeitschrift für Krebsforschung und Klinische Onkologie 76, 1971, pp. 216-218, doi: 10.1007 / BF00303565 .