Trp-EDT and Trp-EDT-TFA adducts
EDT (1,2-ethanedithiol) — added as a scavenger — itself adducts onto Trp's indole C2 position. The +172 Da adduct (Trp-EDT-TFA cyclic dithioacetal) is a characteristic Trp side reaction in EDT-containing cocktails.
- +172 — +172 Da, Trp-EDT-TFA cyclic dithioacetal
- +92 — +92 Da, Trp-EDT
Why it happens (mechanism)
Under TFA, EDT and TFA react to give a thiocarbenium intermediate that adds to indole C2. Ring closure with the second EDT thiol gives a 1,3-dithiolane — Trp gets a saturated 5-membered S-S ring at the 2-position. +172 Da.
When it strikes (triggers)
TFA + EDT cocktail (e.g., reagent K) at elevated temperature (50 °C, e.g., to remove Mtr from Arg). Long cleavage time. Trp residue not Boc-protected.
How to spot it (MS signature)
+172.0 Da. Sometimes paired with simpler +76 (S(CH₂)₂SH) or +92 adducts. Distinguishable from Trp-tBu (+56) by the mass.
How to prevent it
- Trp(Boc) building block — once again, the cure-all for Trp side reactions.
- Reduce EDT to <2.5%; consider replacing with thioanisole or DMS where Mtr/Mtt isn't required.
- Cleavage at room temp, never heated.
- If Mtr removal forced you to elevated temp, switch to Pbf/Pmc on Arg (they cleave cold).
If it already happened (salvage)
- Not reversible.
Source
Yi Yang, Side Reactions in Peptide Synthesis (Elsevier, 2016), Chapter 3, §3.3.