A photolabile protecting group (PPG; also known as: photoremovable, photosensitive, or photocleavable protecting group) is a chemical modification to a molecule that can be removed with light. PPGs enable high degrees of chemoselectivity as they allow researchers to control spatial, temporal and concentration variables with light. Control of these variables is valuable as it enables multiple PPG applications, including orthogonality in systems with multiple protecting groups. As the removal of a PPG does not require chemical reagents, the photocleavage of a PPG is often referred to as "traceless reagent processes", and is often used in biological model systems and multistep organic syntheses. Since their introduction in 1962, numerous PPGs have been developed and utilized in a variety of wide-ranging applications from protein science to photoresists. Due to the large number of reported protecting groups, PPGs are often categorized by their major functional group(s); three of the most common classifications are detailed below.
Historical introduction
The first reported use of a PPG in the scientific literature was by Barltrop and Schofield, who in 1962 used 253.7 nm light to release glycine from N-benzylglycine. Following this initial report, the field rapidly expanded throughout the 1970s as Kaplan and Epstein studied PPGs in a variety of biochemical systems. During this time, a series of standards for evaluating PPG performance was compiled. An abbreviated list of these standards, which are commonly called the Lester rules, or Sheehan criteria are summarized below:
In biological systems, the protected substrate, as well as the photoproducts should be highly soluble in water; in synthesis, this requirement is not as strict The protected substrate, as well as the photoproducts should be stable in the photolysis environment Separation of the PPG should exhibit a quantum yield greater than 0.10 Separation of the PPG should occur through a primary photochemical process The chromophore should absorb incident light with reasonable absorptivity The excitation wavelength of light should be greater than 300 nm The media and photoproducts should not absorb the incident light A general, high-yield synthetic procedure should exist for attaching the PPG to an unprotected substrate The protected substrate and the photoproducts should be easily separated
Main classifications
Nitrobenzyl-based PPGs
Norrish Type II mechanism
Nitrobenzyl-based PPGs are often considered the most commonly used PPGs. These PPGs are traditionally identified as Norrish Type II reaction as their mechanism was first described by Norrish in 1935. Norrish elucidated that an incident photon (200 nm < λ < 320 nm) breaks the N=O π-bond in the nitro-group, bringing the protected substrate into a diradical excited state. Subsequently, the nitrogen radical abstracts a proton from the benzylic carbon, forming the aci-nitro compound. Depending on pH, solvent and the extent of substitution, the aci-nitro intermediate decays at a rate of roughly 102–104 s−1. Following resonance of the π-electrons, a five-membered ring is formed before the PPG is cleaved yielding 2-nitrosobenzaldehyde and a carboxylic acid. Overall, nitrobenzyl-based PPGs are highly general. The list of functional groups that can be protected include, but are not limited to, phosphates, carboxylates, carbonates, carbamates, thiolates, phenolates and alkoxides. Additionally, while the rate varies with a number of variables, including choice of solvent and pH, the photodeprotection has been exhibited in both solution and in the solid-state. Under optimal conditions, the photorelease can proceed with >95% yield. Nevertheless, the photoproducts of this PPG are known to undergo imine formation when irradiated at wavelengths above 300 nm. This side product often competes for incident radiation, which may lead to decreased chemical and quantum yields.
Common modifications In attempts to raise the chemical and quantum yields of nitrobenzyl-based PPGs, several beneficial modifications have been identified. The largest increase in quantum yield and reaction rate can be achieved through substitution at the benzylic carbon. However, potential substitutions must leave one hydrogen atom so the photodegradation can proceeded uninhibited.
Additional modifications have targeted the aromatic chromophore. Specifically, multiple studies have confirmed that the use of a 2,6-dinitrobenzyl PPG increases reaction yield. Additionally, depending on the leaving group, the presence of a second nitro-group may nearly quadruple the quantum yield (e.g. Φ = 0.033 to Φ = 0.12 when releasing a carbonate at 365 nm). While one may credit the increase in efficiency to the electronic effects of the second nitro group, this is not the case. Analogous systems with a 2-cyano-6-nitrobenzyl PPG exhibit similar electron-withdrawing effects, but do not provide such a large increase in efficiency. Therefore, the increase in efficiency is likely due to the increased probability of achieving the aci-nitro state; with two nitro groups, an incoming photon will be twice as likely to promote the compound into an excited state. Finally, changing the excitation wavelength of the PPG may be advantageous. For example, if two PPGs have different excitation wavelengths one group may be removed while the other is left in place. To this end, several nitrobenzyl based PPGs display additional functionality. Common modifications include the use of 2-nitroveratryl (NV) or 6-nitropiperonylmethyl (NP). Both of these modifications induced red-shifting in the compounds' absorption spectra.
Carbonyl-based PPGs
Phenacyl PPGs
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