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at this temperature for 3 min, then H-Val-OMe·HCl (0.5 mmol)
was added and the reaction mixture was stirred at 0 °C for 1 h and
5 h at room temp. Ethyl acetate was added (50 mL) and then
washed with 10% HCl (2ϫ10 mL), Na2CO3 (2ϫ10 mL), and then
satd. NaCl (2ϫ10 mL), dried with a MgSO4 filter and then the
solvent was removed under vacuum to give an oily product which
solidified on standing at room temp. The degree of epimerization
was analyzed by means of HPLC, using Agilent Technologies with
Column Zobrax Eclipse Plus 3.5μ (4.6ϫ100 mm) and 20–50%
CH3CN-H2O, 0.1% TFA gradient in 20 min, with Flow rate =
1 mL/min, λ = 220 nm. tR = 17.82.
General Procedure for Dynamic Differential Scanning Calorimetry
Assays: Samples of benzotriazole and oxime-based additive (1 mg)
were heated from 30–300 °C at a heating rate of 10 °C/min in a
closed high-pressure crucible with N2 flow in a Mettler Toledo
DSC-30 differential scanning calorimeter. Diagrams showing heat
flow as a function of temperature and time were obtained (Fig-
ure 2).
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General Procedure for ARC Experiments: Adiabatic experiments
were carried out in an Accelerating Rate Calorimeter (ARC) from
Thermal Hazard Technology, in ARC TC-HC-MCQ (Hastelloy)
test cells. 0.2 m solutions of additives (4 mL) in DMF were intro-
duced into the calorimetric test cell at room temperature, without
stirring. A test blank of the pressure released by the organic solvent
was also measured. The cell was heated at the initial temperature
(30 °C) and the “heat–wait–seek” method was applied; this con-
sisted of heating the sample by 5 °C and, after 15 min of equilib-
rium, measuring whether self-heating was occurring at a rate higher
than 0.02 °C/min (default sensitivity threshold). When self-heating
was detected, the system was changed to adiabatic mode. After
decomposition, the assay was stopped when the temperature rose
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Supporting Information (see footnote on the first page of this arti-
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synthesized peptides.
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Research in the Albericio laboratory was partially funded by the
Secretaría de Estado de Cooperación Internacional (AECI), the
Centro de Investigación Científica
y Tecnológica (CICYT)
(CTQ2012-30930), the Generalitat de Catalunya (2009SGR 1024)
and the Institute for Research in Biomedicine Barcelona (IRB Bar-
celona)
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Published Online: August 23, 2013
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