E. Bryan Coughlin, PhD , University of Massachusetts (Amherst)
Among the many photolabile groups that have been studied, o-nitrobenzyl (ONB) alcohol derivatives have gained tremendous attention in the area of synthetic organic chemistry and beyond. First described by Schofield and coworkers, the chemistry was not widely recognized until Woodward and coworkers utilized what has become one of the most popular photolabile protecting groups. It is based on the photoisomerization of an o-nitrobenzyl alcohol derivative into a corresponding o-nitrosobenzaldehyde upon irraditation with UV light simultaneously releasing a free carboxylic acid. This mechanism has been investigated in detail, most recently by Wirz and coworkers.
The photodeprotection of ONB esters usually yields carboxylic acids, accompanied by an o-nitrosobenzaldehyde. Fréchet and coworkers demonstrated that the concept could be expanded to yielding organic bases by employing o-nitrobenzyl carbarmates of amines and diamines, which then result in the release of the respective alkylamines. Logically, this chemistry was extended to ONB variants used for alcohol deprotection, and peptide deprotection. 2-Nitrobenzylidene acetals have also been utilized, releasing 1,2-dihydroxy compounds after photolysis and subsequent ester hydrolysis. This chemistry has recently been extended to o-nitrobenzyl triazole linker, prepared by the [2+3] Huisgen cycloaddition or "click" reaction of alkynes and azides, and releasing a free 1,2,3-triazole leaving group. Recent developments have focused on the design of ONB-based protecting groups with a red-shifted absorption to allow photolysis to occur using two-photo excitation techniques.
Other advances in photocleavable junction structure and application include ONB thioxanthone derivatives, which act as intramolecular sensitizers, and the 2-(2-nitrophenyl)propoxycarbonyl (NPPOC) photolabile protecting group, which was developed to address possible issues with photocleavage byproduct photodimerization. Its photocleavage proceeds via a β-elimination mechanism, resulting in a styrenic product that protects against the formation of the expected o-nitrosobenzaldehyde. Other studies focused on the integration of an orthogonal photolysis of different photoprotecting groups, e.g. 3’,5’-dimethoxybenzoin, in conjunction with ONB derivatives.
The application of photolabile molecules, especially ONB derivatives, is not limited to organic synthesis as can be seen by recent developments in biological applications of such photolabile compounds. Photoactivated bioagents, so called “caged compounds”, are an important tool for studying cell signaling events. Consequently, reversible photoswitches have also been investigated. As an example, Chang and coworkers presented a “caged peroxide generator” based on photolysis of an ONB-protected 1,2,4-trihydroxybenzene. This linker can be triggered on demand and was shown to produce H2O2 by reducing molecular oxygen via a superoxide intermediate. Reviews by Heckel, Xing, Zhang, and their respective coworkers have summarized the various applications of caged and light-switchable small molecules (e.g. neuroactive amino acids, steroid hormones, lipids and cellular signaling molecules), proteins and nucleic acids.
Recently, Katz and Burdick have reviewed developments in the area of light-responsive biomaterials, which include the use of the ONB functionality. Besides its focus on biological complexes, it represents the first summary of synthetic polymers that contain ONB moieties. Even though ONB esters have been investigated in polymer science since 1977, it has not been until very recently that studies appeared that take full advantage of this photolabile group in polymer and materials science applications.
We have extended the approach of having photolabile junctions in block copolymers by combing RAFT polymerization and a subsequent inter-macromolecular azide-alkyne click reaction. This novel synthetic methodology provides more flexibility in the synthesis of photocleavable block copolymers. Highly ordered thin films are being prepared, and after photo-etching the resulting nanoporous films can be used to prepare the first examples of nanostructures from a photocleavable polymer template.
The opens the technologically exciting possibility of utilization of ONB junctions to cleave block copolymers upon irradiation, accessing feature sizes that are difficult to achieve with current lithographic techniques. Selective solvent removal of one component generates nanoporous membranes, which can further serve as nanoscopic templates. Further fundamental investigations to enhance photolysis, via increased kinetics or alteration of photolysis wavelength, will permit faster dynamics and system responses. There are certainly untold opportunities to combine the orthogonality of photolability with other chemical transformations and techniques for material manipulation.