Amine Protection and Deprotection

Description: Amines can be protected as carbamate groups using reagents like Boc2O, CBzCl, and FMOC-Cl. These carbamates can be removed using acid (e.g. trifluoroacetic acid for Boc), catalytic hydrogenation (Pd-C, H2 for the CBz group) or basic conditions (piperidine for FMOC) respectively.

Notes: Amine protection is particularly important for peptide synthesis.

Examples:

Notes: Example 1 shows a Boc protection. Examples 2 and 3 show CBz protection. Example 4 shows a Boc deprotection of the amine under acidic conditions which leaves the CBz protected amine unaffected.

Example 5 shows removal of the CBz protecting group from the amine using catalytic hydrogenation.

Mechanism: Protection of amine using Boc₂O (Di-t-butyl dicarbonate).

In the first step, the amine attacks the carbonyl carbon of the carbonate (Step 1, arrows A and B) which forms a new tetrahedral intermediate. Elimination of oxygen (Step 2, arrows C and D) results in loss of a carbonate which itself can act as a base, or spontaneously decarboxylate (lose CO₂) to give t-butoxide, which then neutralizes the protonated carbamate.

This probably oversimplifies things a bit; a proton transfer from the nitrogen to oxygen after Step 1 is also likely and would eventually give the same result, we’re going for simplicity here. 

Deprotection: Protonation of the carbamate oxygen with a strong acid such as trifluoroacetic acid (TFA) (Step 1, arrows A and B) then results in loss of a t-butyl carbocation (Step 2, arrows C and D). The resulting “carbamic acid” (a nitrogen attached to CO2H) undergoes proton transfer (Step 3, arrows E and F)  followed by decarboxylation (Step 4, arrows G and H) to give the neutral, deprotected amine.

Notes: In practice this is one of the simplest reactions to perform in all of organic chemistry. Simply add “neat” TFA to a dilute (~ 0.2 M) solution of your protected amine, and pop! off comes the carbamate. Watching the CO₂ bubble off is very satisfying.

Alternatively, heating the crap out of the protected amine (ca. 180 degrees C under vacuum) will also result in loss of the protecting group.

Real-Life Example:

Org. Synth. 1979, 59, 159

DOI Link: 10.15227/orgsyn.059.0159

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