Photolabile protecting group
A photolabile 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; 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 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. 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 or 6-nitropiperonylmethyl. Both of these modifications induced red-shifting in the compounds' absorption spectra.
Carbonyl-based PPGs
Phenacyl PPGs
The phenacyl PPG is the archetypal example of a carbonyl-based PPG. Under this motif, the PPG is attached to the protected substrate at the αβ-carbon, and can exhibit varied photodeprotection mechanisms based on the phenacyl skeleton, substrate identify and reaction conditions. Overall, phenacyl PPGs can be used to protect sulfonates, phosphates, carboxylates and carbamates.As with nitrobenzyl-based PPGs, several modifications are known. For example, the 3',5'-dimethoxybenzoin PPG contains a 3,5-dimethoxyphenyl substituent on the carbonyl's α-carbon. Under certain conditions, DMB has exhibited quantum yields as high as 0.64. Additionally, the p-hydroxyphenacyl PPG has been designed to react through a photo-Favorskii rearrangement. This mechanism yields the carboxylic acid as the exclusive photoproduct; the key benefit of the pHP PPG is the lack of secondary photoreactions and the significantly different UV absorption profiles of the products and reactants. While the quantum yield of the p-hydroxyphenacyl PPG is generally in the 0.1-0.4 range, it can increase to near unity when releasing a good leaving group such as a tosylate. The photoextrusion of the leaving group from the pHP PPG is so effective, that it also releases even poor nucleofuges such as amines. The Additionally, photorelease occurs on the nanosecond timeframe, with krelease > 108 s−1.
The o-hydroxyphenacyl PPG has been introduced as an alternative with absorption band shifted closer towards the visible region, however it has slightly lower quantum yields of deprotection due to excited state proton transfer available as an alternative deactivation pathway.
The phenacyl moiety itself contains one chiral carbon atom in the backbone. The protected group is not directly attached to this chiral carbon atom, however has been shown to be able to work as a chiral auxiliary directing approach of a diene to a dienophile in a stereoselective thermal Diels–Alder reaction. The auxiliary is then removed simply upon irradiation with UV light.