HATU (1- is(dimethylamino)methylene1H-1,2,3-triazolo ,5-byridinium 3-oxide hexafluorophosphate, Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) is a

reagent In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...

used in

peptide coupling In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl ...

chemistry to generate an active ester from a carboxylic acid. HATU is used along with Hünig's base (''N,N''-diisopropylethylamine, DIPEA), or

triethylamine Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine or tetraethylammonium, for which TEA ...

to form amide bonds. Typically DMF is used as solvent, although other

polar aprotic solvents A polar aprotic solvent is a solvent that lacks an acidic proton and is polar. Such solvents lack hydroxyl and amine groups. In contrast to protic solvents, these solvents do not serve as proton donors in hydrogen bonding In chemistry, a hydro ...

can also be used.

History

HATU was first reported by Louis A. Carpino in 1993 as an efficient means of preparing active esters derived from

1-hydroxy-7-azabenzotriazole 1-Hydroxy-7-azabenzotriazole (HOAt) is a triazole used as a peptide coupling reagent. It suppresses the racemization In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic (opt ...

(HOAt). 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. 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

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 ot 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 Tetramethylurea is the organic compound with the formula (Me2N)2CO. It is a substituted urea. This colorless liquid is used as an aprotic-polar solvent, especially for aromatic compounds and is used e. g. for Grignard reagents. Production The s ...

. Addition of a

nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

, such as an amine, to the OAt-active ester results in acylation. The high coupling efficiencies and fast

reaction rate The reaction rate or rate of reaction is the speed at which a chemical reaction takes place, defined as proportional to the increase in the concentration of a product per unit time and to the decrease in the concentration of a reactant per unit ...

s 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. Mechanism of N-acylation using HATU

Because of the extraordinary coupling efficiency of HATU, it has often been used for intramolecular

amidation In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is p ...

(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. However, HATU should be used in caution for some cases of SPPS as "amino acid building block may be consumed rapidly through lactamization before it is coupled onto the peptide chain".

References

{{reflist Peptide coupling reagents Hexafluorophosphates Triazolopyridines