Disulfide desulfurization (Cys → Ser)

Cystine under HF or harsh acid loses one S, giving Ser-Ser linkage. -32 Da. Old protocol artifact.

Why it happens (mechanism)

Strong acid + radical conditions can desulfurize one S of a disulfide, replacing it with O. Result: -S-O- (mixed disulfide-ester analog) which collapses to two Ser residues.

When it strikes (triggers)

HF cleavage at high concentration, prolonged. Modern Pbf/Trt-protected synthesis rarely sees this. Old Boc/Bzl chemistry.

How to spot it (MS signature)

-32.0 Da. Specifically when both Cys are involved in a disulfide; doesn't affect free Cys.

How to prevent it

• Use Fmoc/tBu chemistry with Trt protection — avoid HF entirely.
• If HF is unavoidable, use 'low-high HF' protocol with thioanisole/cresol scavengers.

If it already happened (salvage)

• Ser is permanent; not reversible to Cys.

Source

Yi Yang, Side Reactions in Peptide Synthesis (Elsevier, 2016), Chapter 9, §9.5; appendix-I.