Visible-light Photoredox Catalysis

Introduction to Photoredox Catalysis

Visible light photoredox catalysis has emerged as a powerful tool in organic synthesis, building upon the foundation set by early pioneers in the areas of radical chemistry and photochemistry. Photoredox chemistry allows one to forge new bonds via open shell pathways and facilitates the rapid assembly of complex products en route to new areas of chemical space. Many transition-metal complexes and organocatalysts capable of initiating radical formation in the presence of visible light have been shown to facilitate a wide array of synthetic transformations including but not limited to cross-coupling, C-H functionalization, alkene and arene functionalization, and trifluoromethylation.

SynLED Parallel Photoreactor

A long-standing challenge in the field of photoredox catalysis is reproducibility between reaction setups as well as across individual reactions performed with the same setup. Our SynLED Parallel Photoreactor (Z742680) seeks to alleviate these issues by enabling small-scale photocatalysis reaction screening as well as rapid library generation while ensuring high levels of consistency across reactions and between runs. The photoreactor allows for 16 simultaneous reactions in 2 dram or smaller scintillation or microwave vials. Each well contains a 1W LED centered at 467.5 nm with a 45 degree lens. A built-in cooling fan and heat sink help maintain reaction temperatures at approximately 30 °C. The setup was designed to fit on a conventional stir plate, including a round cutout to fit firmly on IKA brand stir plates.

Figure 1. Advantages of SynLED Photoreactor

Advantages of SynLED Photoreactor

• 4x4 array accommodates 16 reactions in parallel
• Bottom-lit blue LEDs (465-470 nm) provide consistent light intensity
• Built-in cooling fan provides consistent temperature across reactions

Penn PhD Photoreactor M2

The Penn PhD Photoreactor M2 (Z744035) is a benchtop instrument designed to facilitate consistency and reproducibility in photoredox catalysis across a wide range of reaction scales. The Photoreactor M2 combines LED illumination, mechanical stirring and cooling into one device while accepting reaction vials from 1 mL up to 40 mL. The touch screen user interface allows the chemist to precisely control temperature, intensity, stir rate and time, creating a valuable tool for repeatability, traceability, efficiency, and consistency of results. The Photoreactor M2 addresses the potential to streamline synthetic sequences and create valuable strategies for addressing some of the challenges of molecule construction in drug discovery.

Figure 2. Photoreactor M2

Features of Penn PhD Photoreactor M2

• Modular design allows for use with a variety of wavelengths from 365nm to 450nm
• 360 degree reflective environment maximizes surface area photon capture.
• Light shield interlock prevents user exposure to harmful light rays.
• Interactive touch screen controls reaction parameters
• Intertek ETL, CE, and CB approved.
• User defined parameters including temperature, light intensity, fan speed and stirring.
• Auto stop, pause and reset options
• Supports vial sizes gc, 4, 8, 20, 40 mL
• Temp feedback using a k-type thermocouple

Comparison of Photoreactors

Scale	Up to 40 mL vial	1-2-dram vials	1 mL microvials
# of Simultaneous Reactions	1	16	24
Wavelength	Modular: 450 nm 420 nm 365 nm	465-470 nm	Modular: 470 nm 527 nm white
Max Power	3.4 W	1 W per LED	0.3 W
Variable Light Intensity	Y	N	Y
Lumens	Not measured*	130-140 LM	Not measured
Temperature Control	Built-in fan; 30-50 °C user defined	Built-in fan; 30 °C	None
Stir Rate	100-2000 rpm	For use with external stir plate	For use with external stir plate

*Users have independently reported that the deliverable lumens is 10x of other lab developed or purchased reactor systems.

Representative Catalysts and Applications

Late-Stage Incorporation of Small Alkyl Groups into Small Molecules of Biological Interest

Late-Stage Functionalization (LSF) of small, pharmaceutically active molecules can provide modified potency, toxicity and pharmacokinetic profiles with altogether less effort than the ground-up syntheses of analogs. Though LSF with fluorine (and fluorinated alkyl groups) is now readily achieved through use of, amongst other technologies, the zinc sulfinates developed by the Baran Group at Scripps, the incorporation of small, non-fluorous alkyl groups like methyl and ethyl groups has remained an unmet challenge. This is especially relevant as the incorporation of small alkyl groups is likely to yield molecules with more advantageous physiochemical and safety profiles vis à vis their fluorinated brethren.

Ultimately, the late-stage incorporation of methyl, ethyl and cyclopropyl groups to pharmaceutically active small molecules was achieved through a visible light photoredox strategy. Indeed, in the presence of blue light and peroxide alkyl radical precursors, newly available [Ir{dF(CF₃)ppy}₂(dtbpy)]PF₆ catalyst (747793) mediates the formation of the required alkyl radicals (and thus, alkyl group incorporation) typically achieved by methods not amenable to LSF¹.

Figure 3. Late-Stage Incorporation of Small Alkyl Groups into Small Molecules of Biological Interest

Strategy for Room Temperature Lignin Degradation

Lignin represents over 30% of non-fossil fuel based organic carbon, and as such this biomass could be made, with the advent of chemoselective degradation processes, into a primary source of carbon-based feedstock material. The Stephenson Group has recently combined two of our innovative products to achieve the selective degradation of lignin-type model compounds in one pot. Indeed, Bobbitt’s salt was used to selectively oxidize benzyl alcohols, followed by photocatalytic reductive C-O bond cleavage to the ketone and alcohol degradation products. This last transformation was achieved without degassing and in the presence of visible light².

Figure 3. Strategy for Room Temperature Lignin Degradation

Crossed Intermolecular [2+2] Cycloaddition of Styrenes

The crossed [2 + 2] cycloaddition of styrenes was achieved in high chemoselectivity through use of an appropriately tuned Ru-based visible light photocatalyst. As demonstrated by Prof. Tehshik Yoon, unsymmetrically substituted butanes can thus be prepared on gram scale with Ru(bpm)₃.

Figure 4. Crossed Intermolecular [2+2] Cycloaddition of Styrenes

Diversity of Application

Our visible light photocatalysts have been used in applications that truly span organic chemistry (and beyond). Other reactivities that have been explored include:

• Reduction of unactivated alkyl, alkenyl and aryl iodides
• Co-mediated water oxidation for H₂ gas production
• Atom-transfer radical addition of haloalkanes to alkenes
  
• Formal hydroaminoalkylation of alkenes

References

1. DiRocco DA, Dykstra K, Krska S, Vachal P, Conway DV, Tudge M. 2014. Late-Stage Functionalization of Biologically Active Heterocycles Through Photoredox Catalysis. Angew. Chem. Int. Ed.. 53(19):4802-4806. https://doi.org/10.1002/anie.201402023

2. Nguyen JD, Matsuura BS, Stephenson CRJ. 2014. A Photochemical Strategy for Lignin Degradation at Room Temperature. J. Am. Chem. Soc.. 136(4):1218-1221. https://doi.org/10.1021/ja4113462

3. Ischay MA, Ament MS, Yoon TP. 2012. Crossed intermolecular [2 + 2] cycloaddition of styrenes by visible light photocatalysis. Chem. Sci.. 3(9):2807. https://doi.org/10.1039/c2sc20658g