Scavenger / linker adduct Δm +80 severity: moderate

Side-chain sulfonation (Pbf-derived sulfonyl cation)

Pbf cleavage releases a sulfonyl cation that, if not scavenged, can sulfonate Trp indole, Tyr ring, or other electron-rich aromatics. +80 Da.

Affected residue(s): W Y any nucleophilic side chain

Why it happens (mechanism)

TFA cleavage of Arg(Pbf) gives the Pbf cation, which loses SO₂ and isobutene to regenerate the free guanidino. But under non-ideal conditions (insufficient scavenger, hot TFA), the sulfonyl part (-SO₂-) attaches to a nearby nucleophile — Trp at C2/C5 of the indole, Tyr at C3 of the phenol, even free amines. +80 Da (SO₃H equivalent).

When it strikes (triggers)

Long Arg-rich peptides cleaved without sufficient scavenger (TIS, EDT, anisole). Hot TFA. Concentrated TFA without water.

How to spot it (MS signature)

+80.0 Da. Distinguish from phosphorylation (+80, but Tyr-phospho is biologically meaningful and on hydroxyl, not aromatic carbon). Unique to Arg-containing peptides (Pbf source).

How to prevent it

Standard cocktail TFA/TIS/H₂O/EDT = 92.5/2.5/2.5/2.5 — the EDT and TIS are critical Pbf scavengers.
Increase TIS to 5% for Trp-rich + Arg-rich peptides.
Cleavage at room temp; avoid heating.

If it already happened (salvage)

Sulfonation is permanent.

Source

Yi Yang, Side Reactions in Peptide Synthesis (Elsevier, 2016), Chapter 3, §3.8.