60th Annual Report on Research 2015

Over the past year the Hanson research group has made considerable progress towards our goal of controlling the absolute stereochemistry of organic reactions through a stereoselective excited-state proton transfer (ESPT). As a first step towards this goal a majority of our efforts so far have been focused on demonstrating non-stereoselective ESPT catalyst. Towards this end we have successfully photocatalytically generated 2-phenylcyclohexanone from phenyl-2-(trimethylsiloxy)cyclohexene with 7-bromonaphthol (Br-NpOH) as the ESPT catalyst and phenol as the proton source (Figure below). In this catalytic reaction cycle the excited ESPT catalyst protonates 1-phenyl-2-(trimethylsiloxy)cyclohexene to generate 2-phenylcyclohexanone and Br-NpO^-*. After relaxation, Br-NpO^- is sufficiently basic to be protonated by PhOH to regenerate Br-NpOH which can then, upon excitation, undergo additional reaction cycles.

The reaction goes to near completion (96% yield) under a nitrogen atmosphere with only 1 mol % of Br-NpOH as the photocatalyst. The 96 % product yield indicates that we can achieve at least 96 turnovers per photocatalyst. The reaction does not occur in the absence of light even at elevated temperature and thus the reaction progression can readily be controlled by light modulation. ESPT catalysis is effective with a range of silylenol ethers with both electron donating and electron withdrawing groups. Catalyst screening and the oxygen dependence indicate that proton transfer occurs from triplet excited state of the ESPT catalyst.

Given that the reaction occurs from the triplet excited state of the ESPT dye we incorporated a sensitizer and triplet energy transfer into the catalytic cycle as shown in the Figure below.

Irradiating a solution of 1-phenyl-2-(trimethylsiloxy)cyclohexene, naphthol (50 mol %), SENS (2.5 mol %), and sacrificial acid (AH in excess) with 445 nm light gave product in 74% yield. This reaction yield corresponds to ~30 and ~1.5 turnovers for the sensitizer and ESPT dye, respectively.  The sensitized photocatalytic reaction has several advantages over the unsensitized cycle. The first is that unsubstituted naphthol, which is much more chemically robust and can be found in coal tar, can be used as the ESPT catalyst. The second advantage is that due to the small singlet-triplet gap of SENS can shift the excitation to the visible region and still have sufficient excited state energy to drive the reaction. The above results are first example of an organic transformation via direct and sensitized excited state proton transfer catalysts. These results open the door to an entirely new class of photocatalytic reactions that harness the acidity of excited state proton transfer dyes.

A manuscript containing these results has been submitted and is currently under review for publication in the Journal of the American Chemical Society. Anjan Das, who is the first author on the manuscript, presented these results at the Gordon Research Conference on Photochemistry and his poster received considerable attention from both synthetic organic and photophysical chemists. Additionally, over the past year, Anjan, who came into this research as a synthetic organic chemist, has gained considerable knowledge in molecular photophysics and will have a diverse and relatively unique set of skills as he enters the job market search next year. This is particularly important given the increasing interest in photocatalysis as a green alternative to traditional synthetic organic chemistry.

Upon successfully demonstrating the feasibility of ESPT catalysts, we have shifted our focus to performing the protonation reaction enantioselectively. As outlined in our proposal our first attempts were primarily focused on BINOL derivatives but found that despite several different types of substitution, the dye to planarized and decomposed upon irradiation. As an alternative to BINOL, Br-VANOL ((R)-4,4'-Dibromo-3,3′-Diphenyl-2,2′-bi-1-naphthol) is a molecule that is chiral has alcohol groups, the bromine atoms necessary to access the triplet state and significant steric bulk to prevent planarization. Using Br-VANOL in the place of Br-NpOH in the catalytic cycle above resulted in a 36% yield with a 40 % enantiomeric excess of (S)-2-phenylcyclohexanone as determined by HPLC shown below. As far as we know this is the first demonstration of enantiopreferential protonation of a prochiral substrates via chiral ESPT catalysis.

Current efforts are underway to understand what parameters govern the yield and ee of the reaction (temperature, concentrations, etc.). Recently, the PI was awarded an NSF-Major Research Instrumentation grant to acquire a nanosecond transient absorption spectrometer. This instrument, which will be operational in January will be used to monitor energy transfer and the reaction kinetics for the cycles proposed above. With these insights we anticipate significantly increasing the reaction yield and ee and then expand our substrate scope to include the synthesis of useful fine chemicals like Ibuprofen and others. We are also working to incorporate sensitizer into the enantioselective ESPT reaction cycle to perform the reaction with VANOL (without bromine substitution). This grant has provided us with the necessary preliminary results for the PI to apply for, and have a strong chance at obtaining, NSF funding next summer (NSF-CAREER) and fall (NSF-CHE). Due to my limited number of graduate students, this project is currently being pursued by a postdoctoral researcher in my lab. However, with the promising results above I am actively recruiting incoming graduate students to pursue this research project.