[molecular-world]

Can anyone please explain why TFA is used to de-protect the Boc group on the alpha amine but HF is used for cleavage from resin in SPPS? TFA is a stronger acid (pKa 0.23) than HF (3.2). It sounds like the TFA should also be able to just cleave it off the resin as well. Maybe it depends on the linker... I would appreciate the help a lot! Thanks.

[BobfromNC]

Depends what resin you are using.   Some resins are designed for use with TFA to cleave the peptide from the resin, most use FMOC amino acids and deprotection chemistry for the synthesis part.    The resins used for Bocamino acids have very stable linkers, which are stable to TFA (used to take the Boc off) but can be cleaved using anhydrous HF.  Keep in mind that acidity is not quite the same measurements when not in water, so comparing HF and TFA is not as simple as Pkas based on aqueous conditions.  And HF will also remove CBZ and Boc groups as well.   

I would warn people that using HF for this is not easy, which is why most people sue Fmoc chemistry and TFA to cleave the final product.    That also allows the side groups to be protected with Boc and other acid labile groups, which are easily removed with TFA (which is also pretty nasty to work with if you are not careful.)