HATU

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Structural formula
Structural formula of HATU
Uronium salt (= O form of HATU)
General
Surname HATU
other names
  • 1- [bis (dimethylamine) methylene] -1 H -1,2,3-triazolo [4,5- b ] pyridinium 3-oxide hexafluorophosphate
  • O - (7-Azabenzotriazol-1-yl) - N , N , N ′, N ′ -tetramethyluronium hexafluorophosphate
Molecular formula C 10 H 15 F 6 N 6 OP
Brief description

light brown crystalline solid

External identifiers / databases
CAS number 148893-10-1
EC number 604-662-7
ECHA InfoCard 100.112.881
PubChem 9886157
Wikidata Q5628980
properties
Molar mass 380.23 g mol −1
Physical state

firmly

Melting point

183-185 ° C (N-shape)

safety instructions
GHS labeling of hazardous substances
02 - Highly / extremely flammable 07 - Warning

danger

H and P phrases H: 228-315-319-335
P: 210-261-305 + 351 + 338
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

HATU [ O - (7-Azabenzotriazol-1-yl) - N , N , N ', N ' -tetramethyluronium hexafluorophosphate] is a coupling reagent that is used in organic chemistry and biochemistry for peptide synthesis and in general for coupling amino acids . The compound is classified as explosive according to the SprengG and was assigned to substance group C.

properties

structure

Guanidinium Salt ( N -form from HATU)

HATU can exist in two forms, the uronium salt ( O form) or the preferred but less reactive iminium salt ( N form). When synthesizing from 1-hydroxy-7-azabenzotriazole (HOAt), the presence of tertiary amines must be excluded, as these catalyze the conversion of the uronium form into the N form . The O form can be generated in the synthesis by using 1-potassiumoxy-7-azabenzotriazole instead of 1-hydroxy-7-azabenzotriazole and is used rapidly to avoid isomerization . The comparatively high reaction rate is probably due to a neighboring group effect due to the nitrogen atom of the pyridine ring, which stabilizes the attacking amine with a seven- atom ring closed via a hydrogen bond . The O form can be rearranged into the N form by the action of triethylamine .

Reactions

By reacting HATU with amino acids, activated amino acids are generated in a first step with the release of tetramethylurea ( transition state O -acyl (tetramethyl) isouronium salt), which react readily with other amino acids in the second step.

Mechanism of N acylation with HATU

HATU can generally be used for acylation reactions of alcohols or amines ; the reaction products are esters or amides . With HATU, amine-modified nucleic acids can be coupled to proteins or peptides . HATU is mostly used in the presence of the Hünig base ( N , N -diisopropylethylamine, DIPEA) and the solvent dimethylformamide . To avoid racemization , HBTU , HCTU , TBTU , COMU , TOMBU or COMBU are often used as alternatives .

history

HATU was first described in 1993 by Louis A. Carpino.

Individual evidence

  1. ↑ a b c d e data sheet HATU, ≥98.0% (CHN) from Sigma-Aldrich , accessed on August 1, 2014 ( PDF ).
  2. ↑ LP Miranda, PF Alewood: Accelerated chemical synthesis of peptides and small proteins. In: Proceedings of the National Academy of Sciences of the United States of America . Volume 96, Number 4, February 1999, pp. 1181-1186, PMID 9989998 . PMC 15437 (free full text).
  3. ↑ Announcement of the new findings made by BAM since 1987 in accordance with § 2 SprengG - notification of assessment no. 457 of December 20, 2006 pdf link .
  4. ↑ Louis A. Carpino, Hideko Imazumi, Ayman El-Faham, Fernando J. Ferrer, Chongwu Zhang, Yunsub Lee, Bruce M. Foxman, Peter Henklein, Christiane Hanay, Clemens Mügge, Holger Wenschuh, Jana Klose, Michael Beyermann, Michael Bienert : The Uronium / Guanidinium Peptide Coupling Reagents: Finally the True Uronium Salts. In: Angewandte Chemie International Edition. 41, 2002, pp. 441-445, doi : 10.1002 / 1521-3773 (20020201) 41: 3 <441 :: AID-ANIE441> 3.0.CO; 2-N .
  5. ↑ Louis A. Carpino, Hideko Imazumi, Bruce M. Foxman, Michael J. Vela, Peter Henklein, Ayman El-Faham, Jana Klose, Michael Bienert: Comparison of the Effects of 5- and 6-HOAt on Model Peptide Coupling Reactions Relative to the Cases for the 4- and 7-Isomers. In: Organic Letters. 2, 2000, pp. 2253-2256, doi: 10.1021 / ol006013z .
  6. ↑ JG Aaronson, LJ Klein, AA Momose, AM O'Brien, AW Shaw, TJ Tucker, Y. Yuan, DM Tellers: Rapid HATU-mediated solution phase siRNA conjugation. In: Bioconjugate Chemistry . Volume 22, Number 8, August 2011, pp. 1723-1728, doi: 10.1021 / bc2001227 . PMID 21744777 .
  7. ↑ CU Hjørringgaard, A. Brust, PF Alewood: Evaluation of COMU as a coupling reagent for in situ neutralization Boc solid phase peptide synthesis. In: Journal of peptide science: an official publication of the European Peptide Society. Volume 18, Number 3, March 2012, pp. 199-207, doi: 10.1002 / psc.1438 , PMID 22252935 .
  8. ↑ R. Subirós-Funosas, L. Nieto-Rodriguez, KJ Jensen, F. Albericio: COMU: scope and limitations of the latest innovation in peptide acyl transfer reagents. In: Journal of peptide science: an official publication of the European Peptide Society. Volume 19, Number 7, July 2013, pp. 408-414, doi: 10.1002 / psc.2517 , PMID 23712932 .
  9. ↑ YE Jad, SN Khattab, BG de la Torre, T. Govender, HG Kruger, A. El-Faham, F. Albericio: TOMBU and COMBU as Novel Uronium-type peptide coupling reagents derived from Oxyma-B. In: Molecules . Volume 19, number 11, 2014, pp. 18953-18965, doi: 10.3390 / molecules191118953 , PMID 25412042 .
  10. ↑ Louis A. Carpino: 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive. In: Journal of the American Chemical Society. 115, 1993, pp. 4397-4398, doi: 10.1021 / ja00063a082 .