Acetone-induced N-terminal imidazolidinone

Trace acetone (lab-grade or rotavap residue) condenses with N-terminal amine → Schiff base → cyclizes onto residue 2's backbone amide → 5-membered 2,2-dimethyl-imidazolidinone. +40 Da.

Why it happens (mechanism)

Acetone + Nα → carbinolamine → dehydration → Schiff base. The C=N is electrophilic; backbone amide N of residue 2 attacks intramolecularly (5-exo-trig), forming a 2,2-dimethyl-imidazolidinone ring. +40.03 Da.

When it strikes (triggers)

Acetone-rinsed glassware not fully dried. Aminooxy peptides with even trace acetone (oxime formation, also +40). Storage in plastic tubes whose softener leaches acetaldehyde/acetone. Discovered in oxytocin synthesis classically.

How to spot it (MS signature)

+40.03 Da. Common with N-terminal residues whose residue-2 backbone amide is freely accessible (no Pro at position 2, etc.).

How to prevent it

• Never rinse glassware with acetone for peptide work. Use only methanol (and dry it).
• For aminooxy peptides: use carbonyl scavengers (e.g., aminooxyacetic acid) in storage solutions, work under Ar, freshly distilled diethyl ether.
• Use freshly opened ether/DCM for cleavage workup.
• Store peptides under inert atmosphere, in cleanroom-grade containers.

If it already happened (salvage)

• Imidazolidinone hydrolyzes slowly under acidic conditions (pH 2, hot, hours) but yields are poor and risk other damage. Re-synthesize.

Source

Yi Yang, Side Reactions in Peptide Synthesis (Elsevier, 2016), Chapter 14, §14.5.