Wikipedia

HBTU

HBTU (Hexafluorophosphate Benzotriazole Tetramethyl Uronium) is a coupling reagent used in solid phase peptide synthesis. It was introduced in 1978 and shows resistance against racemization.[3][4] It is used because of its mild activating properties.[5]

HBTU
HBTU Structural Formula
Names
IUPAC name
[benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate[1]
Other names
  • HBTU

  • 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

  • 3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.133.815 Edit this at Wikidata
EC Number
  • 619-076-7
UNII
  • InChI=1S/C11H16N5O.F6P/c1-14(2)11(15(3)4)17-16-10-8-6-5-7-9(10)12-13-16;1-7(2,3,4,5)6/h5-8H,1-4H3;/q+1;-1
    Key: UQYZFNUUOSSNKT-UHFFFAOYSA-N
  • CN(C)C(=[N+](C)C)ON1C2=CC=CC=C2N=N1.F[P-](F)(F)(F)(F)F
Properties
C11H16F6N5OP
Molar mass 379.247 g·mol−1
Appearance White crystals
Melting point 200 °C (392 °F; 473 K)
Hazards[2]
Occupational safety and health (OHS/OSH):
Main hazards
 Irritant
GHS labelling:
GHS07: Exclamation mark
Warning
H315, H319, H335
P210, P240, P241, P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P332+P313, P337+P313, P362, P370+P378, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

HBTU is prepared by reaction of HOBt with TCFH under basic conditions[6] and was assigned to a uronium type structure, presumably by analogy with the corresponding phosphonium salts, which bear a positive carbon atom instead of the phosphonium residue. Later, it was shown by X-ray analysis that salts crystallize as aminium rather than the corresponding uronium salts.[7][8]

Mechanism

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This scheme depicts the general mechanistic steps of HBTU creating an activated ester out of the carboxylate anion of the acid substrate. The deprotination of the carboxylic acid and the aminolysis of the activated ester are not shown.

HBTU activates carboxylic acids by forming a stabilized HOBt (Hydroxybenzotriazole) leaving group. The activated intermediate species attacked by the amine during aminolysis is the HOBt ester.

To create the HOBt ester, the carboxyl group of the acid attacks the imide carbonyl carbon of HBTU. Subsequently, the displaced anionic benzotriazole N-oxide attacks of the acid carbonyl, giving the tetramethyl urea byproduct and the activated ester. Aminolysis displaces the benzotriazole N-oxide to form the desired amide.[9]

Safety

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In vivo dermal sensitization studies according to OECD 429[10] confirmed HBTU is a moderate skin sensitizer, showing a response at 0.9 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.[11] Thermal hazard analysis by differential scanning calorimetry (DSC) shows HBTU is potentially explosive.[12]

See also

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References

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  1. ^ CID 2733084 from PubChem
  2. ^ "2-(1h-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate". pubchem.ncbi.nlm.nih.gov.
  3. ^ Dourtoglou, Vassilis. (April 1978). "L'hexafluorophosphate de O-benzotriazolyl-N,N-tetramethyluronium: Un reactif de couplage peptidique nouveau et efficace". Tetrahedron Letters. 19 (15): 1269–1272. doi:10.1016/0040-4039(78)80103-8.
  4. ^ Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. (1989). "New coupling reagents in peptide chemistry". Tetrahedron Letters. 30 (15): 1927–1930. doi:10.1016/S0040-4039(00)99616-3.
  5. ^ Solange, A. (1992). "HBTU: a mild activating agent of muramic acid". Bioorganic & Medicinal Chemistry Letters. 2 (6): 571–574. doi:10.1016/S0960-894X(01)81199-9.
  6. ^ WO1994007910A1, Carpino, Louis A., "New reagents for peptide couplings", issued 1994-04-14 
  7. ^ Carpino, L.; Imazumi, H.; El-Faham, A.; Ferrer, F.; Zhang, C.; Lee, Y.; Foxman, B.; Henklein, P.; Hanay, C.; Mügge, C.; Wenschuh, H.; Klose, J.; Beyermann, M.; Bienert, M. (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.
  8. ^ Abdelmoty, I.; Albericio, F.; Carpino, L.; Foxman, B.; Kates, S. (1994). "Structural studies of reagents for peptide bond formation: Crystal and molecular structures of HBTU and HATU". Letters in Peptide Science. 1 (2): 57–67. doi:10.1007/BF00126274. S2CID 38746650.
  9. ^ Bradley, Mark; Valeur, Eric (2009-01-26). "Amide bond formation: beyond the myth of coupling reagents". Chemical Society Reviews. 38 (2): 606–631. doi:10.1039/B701677H. ISSN 1460-4744. PMID 19169468.
  10. ^ OECD (2010). Test No. 429: Skin Sensitisation: Local Lymph Node Assay. Paris: Organisation for Economic Co-operation and Development.
  11. ^ 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.
  12. ^ 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.
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