9fluorenylmethyloxycarbonyl

9-fluorenylmethoxycarbonyl (Fmoc) is a carbamate-based protecting group for amines, widely used in solid-phase peptide synthesis (SPPS) and solution-phase peptide synthesis. The group is base-labile, enabling N-terminal deprotection with mild secondary amines, while the rest of the molecule remains stable under acidic conditions used for side-chain protection and resin cleavage. Fmoc was introduced by Carpino and Han in the early 1970s as an alternative to the Boc/tBu strategy.

The Fmoc group derives from the fluorenylmethyl framework and carries a chromophore that absorbs in the ultraviolet region (around 290–300 nm), allowing convenient monitoring of deprotection steps by UV spectroscopy. The 9-position of the fluorenyl ring provides the characteristic absorption and contributes to its predictable fragmentation behavior during deprotection.

Deprotection is base-mediated and typically performed with 20% piperidine in dimethylformamide (DMF) or dimethyl sulfoxide (DMSO). Removal proceeds via beta-elimination to release carbon dioxide and dibenzofulvene, which rapidly traps with the amine or scavengers present to form stable adducts, minimizing side reactions.

SPPS advantages include compatibility with acid-labile side-chain protections, milder deprotection environments compared with Boc chemistry, and convenient monitoring via UV. It is widely used for assembling peptides, including difficult sequences, and in combinatorial libraries. Fmoc chemistry often requires careful solvent and base choice to minimize aggregation and racemization.

Limitations and considerations include potential base sensitivity for certain residues and the possibility of dibenzofulvene-related side reactions if scavengers are inadequate. In practice, optimized scavenger systems and alternative deprotection conditions are employed to mitigate these issues.