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Reactions >> Protecting Groups >> Stability

Protecting Groups

Stability data for the most frequently used protective groups, protection and deprotection methods

Functional Groups:

 

 Amino 9-Fluorenylmethyl carbamate (Fmoc-NRR') t-Butyl carbamate (Boc-NRR')
>> Stability
Benzyl carbamate (Z-NRR', Cbz-NRR') Acetamide Trifluoroacetamide
Phthalimide Benzylamine (Bn-NRR') Triphenylmethylamine (Tr-NRR')
Benzylideneamine p-Toluenesulfonamide (Ts-NRR')
  
Carbonyl Dimethyl acetal 1,3-Dioxane
>> Stability
1,3-Dithiane N,N-Dimethylhydrazone
  
Carboxyl Methyl ester t-Butyl ester
>> Stability
Benzyl ester S-t-Butyl ester 2-Alkyl-1,3-oxazoline
  
Hydroxyl Methoxymethyl ether (MOM-OR) Tetrahydropyranyl ether (THP-OR)
>> Stability
t-Butyl ether Allyl ether Benzyl ether (Bn-OR)
t-Butyldimethylsilyl ether (TBDMS-OR) t-Butyldiphenylsilyl ether (TBDPS-OR) Acetic acid ester
Pivalic acid ester Benzoic acid ester
 
1,2-; 1,3-Diols Acetonide Benzylidene acetal
>> Stability

What are protective groups?

A protective group (also referred to as "protecting group") is a reversably formed derivative of an existing functional group in a molecule. The protective group is temporarily attached to decrease reactivity so that the protected functional group does not react under synthetic conditions to which the molecule is subjected in one or more subsequent steps. As an example, whereas amines are nucleophiles and react with electrophiles, the amino group is no longer nucleophilic after being converted to a carbamate. Protecting an amine as a carbamate therefore enables other functional groups to undergo selective reactions with electrophiles whereby the carbamate (protected amino group) is left intact. However, two additional synthetic steps are needed to achieve this protection: the step to form the protected intermediate and a deprotection once the additional selective synthetic steps have been completed. In addition, the nature of the protective group must be chosen carefully to ensure adequate stability throughout all the intermediary synthesis steps. Moreover, the conditions for the protection and deprotection steps and the nature of the protective group itself mustn't interfere with other functional groups present in the molecule.

If more than one functional group of the same type is present in a molecule, subtle differences in reactivity - for example caused by steric effects - can help to achieve the selective protection of just one functional group while another such functional group remains unprotected. Alternatively, a second such functional group could be protected with a different protecting group that has a different reactivity profile. Another opportunity is to build a larger molecule from subunits in which similar or identical functional groups have been differently protected beforehand. For example, a Boc-protected amino group can be deprotected in acidic media, whereas a Fmoc-protected amino group can be deprotected under basic conditions. The presence of both protective groups in the same molecule therefore enables selective deprotection of one protected amino group for a further reaction while the second protected amino group remains untouched. This is referred to as an orthogonal protecting group strategy.

Not only is selectivity important, but the yields for the protection and deprotection steps must be high to avoid making the reaction sequence inefficient. As a result, chemists in recent years prefer to design synthesis pathways that employ steps conducted under more selective reaction conditions, engineered to affect and convert only the specific desired functional group rather than harsher, less selective conditions that require protection for differentiation. Another tactic is to employ reaction conditions under which the functional group "protects itself" temporarily, for example as an anion under basic conditions or a cation under acidic conditions. These minimalist approaches can be summarized in the statements that, "the best protective group is no protective group", and "the best protective group is the one that isn't required". The demands of designing environmentally friendly ("green") synthesis pathways, or simply more efficient synthesis pathways with fewer steps and higher overall yields, have resulted in a number of reports of synthetic sequences to produce natural compounds or other synthesis targets that are fully protective group-free.