Benzyl chloroformate is commonly used in organic synthesis for the introduction of the benzyloxycarbonyl (formerly called carboxybenzyl) protecting group for amines. The protecting group is abbreviated Cbz or Z (in honor of discoverer Zervas), hence the alternative shorthand designation for benzyl chloroformate as Cbz-Cl or Z-Cl.
Benzyloxycarbonyl is a key protecting group for amines, suppressing the nucleophilic and basic properties of the N lone pair. This "reactivity masking" property, along with the ability to prevent racemization of Z-protected amines, made the Z group the basis of the Begmann-Zervas synthesis of oligopeptides (1932) where the following general reaction is performed to protect the N-terminus of a serially growing oligopeptide chain:
This reaction was hailed as a "revolution" and essentially started the distinct field of synthetic peptide chemistry. It remained unsurpassed in utility for peptide synthesis until the early 1950s when mixed anhydride and active ester methodologies were developed.
Although the reaction is no longer commonly used for peptides, it is nonetheless very widespread for amine protection in other applications within organic synthesis and total synthesis. Common procedures to achieve protection starting from benzyl chloroformate include:
* Benzyl chloroformate and a base, such as sodium carbonate in water at 0 °C
* Benzyl chloroformate and magnesium oxide in ethyl acetate at 70 °C to reflux
* Benzyl chloroformate, DIPEA, acetonitrile and scandium trifluoromethanesulfonate (Sc(OTf))
Alternatively, the Cbz group can be generated by the reaction of an isocyanate with benzyl alcohol (as in the Curtius rearrangement).