Singlet oxygen-mediated selective C–H bond hydroperoxidation of ethereal hydrocarbons

Singlet O2 is a key reactive oxygen species responsible for photodynamic therapy and is generally recognized to be chemically reactive towards C=C double bonds. Herein, we report the hydroperoxidation/lactonization of α-ethereal C–H bonds by singlet O2 (1Δg) under exceptionally mild conditions, i.e., room temperature and ambient pressure, with modest to high yields (38~90%) and excellent site selectivity. Singlet O2 has been known for > 90 years, but was never reported to be able to react with weakly activated C–H bonds in saturated hydrocarbons. Theoretical calculations indicate that singlet O2 directly inserts into the α-ethereal C–H bond in one step with conservation of steric configuration in products. The current discovery of chemical reaction of singlet oxygen with weakly activated solvent C–H bonds, in addition to physical relaxation pathway, provides an important clue to a 35-year-old unresolved mystery regarding huge variations of solvent dependent lifetime of singlet O2.


Selective oxidative alpha ethereal C-H functionalization of pitofenone.
A dry test tube (20 mL) with rubber septum and magnetic stirrer bar was charged with pitofenone 1t (1 mmol), and then bubbled with dry oxygen for 10 minutes before addition of 1 x 10 -5 M of photosensitizer (meso-TPP) and 10 mol% of Lewis acid ( ϒ-Al 2 O 3 ). The solution was then irradiated using a blue-LEDs array at room temperature (25-28 o C) under an 1 atm oxygen atmosphere for 20 h. The reaction mixture was diluted with ethyl acetate-hexane (4:6 volume ratio), and stirred for 10 min. The mixture was filtered through celite, silica gel pads, and washed with ethyl acetate. The filtrate was concentrated using a rotary evaporator. The residue products were purified by column chromatography on silica gel and collected as pasty form. The collected product was dissolved in ether, followed by slow addition of HCl in ether under stirring for 2 h at room temperature.
Finally, the solid product (3t) was collected by filtration. 8 . THF-d 8 was used as a starting material to react with singlet oxygen, which leads to the production of THF-d 8 peroxide in 8% yield after 15 h irradiation using a 100 W Hg lamp. The yield (8%) of THF-d 8 hydroperoxide is significant lower than that (35%) of the THF-H 8 hydroperoxide under the same condition, which is due to the stronger C-D bond than the C-H bond and is consistent with the expected kinetic isotope effect.

Spectroscopic Data.
Hydroperoxy-tetrahydrofuran (2a) 1 NMR data (3a) is in agreement with authentic commercially available sample. 3 19.4. NMR data of (2b) was identical with that in the literature 3 . (  NMR data of (2k) was identical with that in the literature 6,7 . NMR data of (3l) was identical with that in the literature 8 . NMR data of (3m) was identical with commercially available authentic material and with that in the literature 9 .
Isochroman-1-one (3n) 11  NMR data of (3n) was identical with commercially available authentic material and with that in the literature 11 . 12  NMR data of (3o) was identical with commercially available authentic material and with that in the literature 12 . 13  NMR data of (2p) was identical with that in the literature 13 .

Measurements of enantiomeric excess (ee) by chiral gas chromatography.
Instrumentation: Gas Chromatography analysis were carried out using GC-2014 SHIMADZU gas-chromatograph (serial no: C11484301285SA) equipped with a FID detector and a fused silica capillary column. The carrier gas was high purity grade nitrogen (N 2 ).
Column: Fused silica tubing (undeactivated, untreated) with 60 m x 0.53 mm (serial no: 1406465) was purchased from RESTEK GC Columns. Prior to use, the column was washed with n-hexane, chloroform (purified by basic alumina), acetone, and water. The cleaning procedure was repeated once in a reverse order.       In CCl 4 , the physical deactivation rate, k 0 value, is 1/(900 μs)=1.1 x 10 3 s -1 . In neat THF, the k 0 value is assumed to be (13/4= 3.25) times faster than for CCl 4 , since THF has 13 (C-H, C-C or C-O) single bonds when compared to 4 C-Cl single bonds for CCl 4 . To the first approximation, this assumption is valid since solvent nuclear vibrational motion is the main exit channel responsible for the physical deactivation (via electronic-vibrational coupling) of singlet O 2 . Therefore, the k 0 value for THF is tentatively assumed to be approximately 1.1 x 10 3 s -1 x 3.25= 3.6 x 10 3 s -1 . From the competition reaction with 1-methylcyclohexene, we obtained the chemical reaction rate of singlet O 2 with THF to be 3.8 x 10 3 M -1 s -1 . Neat THF has a THF concentration of 12.35 M. Therefore, the chemical quantum yield of product formation for singlet O 2 chemical reaction with THF can be obtained by the Supplementary Equation (6) Purification of starting materials. Starting materials were purchased at the highest commercial quality and further purification by distillation process or activated alumina column chromatography. Low boiling liquid starting materials (1a-1k) were purified by distillation process (distillation procedure followed by known literature methods). Aromatic Starting materials (1l-1r) were purified by passing through activated alumina column chromatography under N 2 atmosphere. As requested by one of the reviewer, we have attached the 1 H-NMR of purified starting materials (See Supplementary Figures 39-53