HATU
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| Names | |
|---|---|
| IUPAC name 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate | |
| Identifiers | |
3D model (JSmol) | |
| ChemSpider | |
| ECHA InfoCard | 100.103.434 |
PubChem CID | |
| UNII | |
CompTox Dashboard (EPA) | |
| |
| |
| Properties | |
| C10H15F6N6OP | |
| Molar mass | 380.235 g·mol−1 |
| Appearance | White crystalline solid |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
HATU (Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) is a reagent used in peptide coupling chemistry to generate an active ester from a carboxylic acid. HATU is used along with Hünig's base (N,N-diisopropylethylamine), or triethylamine to form amide bonds. Typically DMF is used as solvent, although other polar aprotic solvents can also be used.[1]
History
[edit]HATU was first reported by Louis A. Carpino in 1993 as an efficient means of preparing active esters derived from 1-hydroxy-7-azabenzotriazole (HOAt).[2] HATU is commonly prepared from HOAt and TCFH under basic conditions[3] and can exist as either the uronium salt (O-form) or the less reactive iminium salt (N-form). HATU was initially reported as the O-form using the original preparation reported by Carpino; however, X-ray crystallographic and NMR studies revealed the true structure of HATU to be the less reactive guanidinium isomer.[4] It is, however, possible to obtain the uronium isomer by preparing HATU using KOAt in place of HOAt and working up the reaction mixture quickly to prevent isomerisation.
Reactions
[edit]HATU is commonly encountered in amine acylation reactions (i.e., amide formation). Such reactions are typically performed in two distinct reaction steps: (1) reaction of a carboxylic acid with HATU to form the OAt-active ester; then (2) addition of the nucleophile (amine) to the active ester solution to afford the acylated product.
The reaction mechanism of carboxylic acid activation by HATU and subsequent N-acylation is summarised in the figure below. The mechanism is shown using the more commonly encountered and commercially available iminium isomer; a similar mechanism, however, is likely to apply to the uronium form. In the first step, the carboxylate anion (formed by deprotonation by an organic base [not shown]) attacks HATU to form the unstable O-acyl(tetramethyl)isouronium salt. The OAt anion rapidly attacks the isouronium salt, affording the OAt-active ester and liberating a stoichiometric quantity of tetramethylurea. Addition of a nucleophile, such as an amine, to the OAt-active ester results in acylation.
The high coupling efficiencies and fast reaction rates associated with HATU coupling are thought to arise from a neighbouring group effect brought about by the pyridine nitrogen atom, which stabilises the incoming amine through a hydrogen-bonded 7-membered cyclic transition state.[5]
Because of the extraordinary coupling efficiency of HATU, it has often been used for intramolecular amidation (coupling of a carboxylic acid and an amine of the same molecule). For example, the formation of cyclo-tetrapeptides through the head-to-tail reaction of linear tetrapeptides assisted by HATU has been reported.[6]
Safety
[edit]HATU has been shown to induce allergic reactions.[7] In vivo dermal sensitization studies according to OECD 429[8] confirmed HATU is a moderate skin sensitizer, showing a response at 1.2 wt% in the Local Lymph Node Assay (LLNA) placing it in Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Dermal Sensitization Category 1A.[9] Thermal hazard analysis by differential scanning calorimetry (DSC) shows HATU is potentially explosive.[10]
References
[edit]- ^ "Amine to Amide (Coupling) - HATU".
- ^ Carpino, Louis A (1993). "1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive". Journal of the American Chemical Society. 115 (10): 4397–4398. doi:10.1021/ja00063a082.
- ^ WO1994007910A1, Carpino, Louis A., "New reagents for peptide couplings", issued 1994-04-14
- ^ Carpino, Louis A; Imazumi, Hideko; El-Faham, Ayman; Ferrer, Fernando J; Zhang, Chongwu; Lee, Yunsub; Foxman, Bruce M; Henklein, Peter; Hanay, Christiane; Mügge, Clemens; Wenschuh, Holger; Klose, Jana; Beyermann, Michael; Bienert, Michael (2002). "The Uronium/Guanidinium Peptide Coupling Reagents: Finally the True Uronium Salts". Angewandte Chemie International Edition. 41 (3): 441–445. doi:10.1002/1521-3773(20020201)41:3<441::AID-ANIE441>3.0.CO;2-N. PMID 12491372.
- ^ Carpino, Louis A; Imazumi, Hideko; Foxman, Bruce M; Vela, Michael J; Henklein, Peter; El-Faham, Ayman; Klose, Jana; Bienert, Michael (2000). "Comparison of the Effects of 5- and 6-HOat on Model Peptide Coupling Reactions Relative to the Cases for the 4- and 7-Isomers†,‡". Organic Letters. 2 (15): 2253–2256. doi:10.1021/ol006013z. PMID 10930256.
- ^ Müntener, Thomas; Thommen, Fabienne; Joss, Daniel; Kottelat, Jérémy; Prescimone, Alessandro; Häussinger, Daniel (16 April 2019). "Synthesis of chiral nine and twelve-membered cyclic polyamines from natural building blocks" (PDF). Chemical Communications. 55 (32): 4715–4718. doi:10.1039/C9CC00720B. ISSN 1364-548X.
- ^ McKnelly, Kate J.; Sokol, William; Nowick, James S. (2020-02-07). "Anaphylaxis Induced by Peptide Coupling Agents: Lessons Learned from Repeated Exposure to HATU, HBTU, and HCTU". The Journal of Organic Chemistry. 85 (3): 1764–1768. doi:10.1021/acs.joc.9b03280. ISSN 0022-3263.
- ^ OECD (2010). Test No. 429: Skin Sensitisation: Local Lymph Node Assay. Paris: Organisation for Economic Co-operation and Development.
- ^ Graham, Jessica C.; Trejo-Martin, Alejandra; Chilton, Martyn L.; Kostal, Jakub; Bercu, Joel; Beutner, Gregory L.; Bruen, Uma S.; Dolan, David G.; Gomez, Stephen; Hillegass, Jedd; Nicolette, John; Schmitz, Matthew (2022-06-20). "An Evaluation of the Occupational Health Hazards of Peptide Couplers". Chemical Research in Toxicology. 35 (6): 1011–1022. doi:10.1021/acs.chemrestox.2c00031. ISSN 0893-228X. PMC 9214767. PMID 35532537.
- ^ Sperry, Jeffrey B.; Minteer, Christopher J.; Tao, JingYa; Johnson, Rebecca; Duzguner, Remzi; Hawksworth, Michael; Oke, Samantha; Richardson, Paul F.; Barnhart, Richard; Bill, David R.; Giusto, Robert A.; Weaver, John D. (2018-09-21). "Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing". Organic Process Research & Development. 22 (9): 1262–1275. doi:10.1021/acs.oprd.8b00193. ISSN 1083-6160.