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HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 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, DIPEA) to form amide bonds. Generally DMF is used as solvent, although other polar organic solvents can also be used.

HATU
HATU PF6 - iminium isomer.png
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 100.112.881
Properties
C10H15F6N6OP
Molar mass 380.24 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).
Infobox references

HistoryEdit

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).[1] HATU 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.[2] 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.

ReactionsEdit

HATU is commonly encountered in alcohol and amine acylation reactions (i.e., ester and 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 (e.g., alcohol or 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.[3]

 
Mechanism of N-acylation using HATU

ReferencesEdit

  1. ^ Carpino, Louis A (1993). "1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive". Journal of the American Chemical Society. 115 (10): 4397. doi:10.1021/ja00063a082.
  2. ^ 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. doi:10.1002/1521-3773(20020201)41:3<441::AID-ANIE441>3.0.CO;2-N. PMID 12491372.
  3. ^ 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. doi:10.1021/ol006013z. PMID 10930256.