They do several clever things in that paper. I imagine the oxidation works by chlorination, first, then by removal of the HCl group, which would be absorbed by base, neatly removing two hydrogens, and changing a -OH to a =O. If this could work on hydroquinones....well, I get ahead of myself. Anyway, the major competing reaction that lowers yield is chlorination of the ketone. So they put the mixture in an excess of acetone, which is a ketone, so the acetone will compete for the chlorination, saving your precious material and raising yields. Pretty cool, actually.
This paper is cool because they actually do p2p-ol to p2p. No extrapolation needed.
Ning strongly suspects the pyridine could be replaced with Na2CO3 or some such thing as that.
Synthetic communications, 22(11), 1589 (1992)
The oxidation of secondary alcohols to ketones with trichloroisocyanuric acid
Gene A. Hiegel and Malekashtar Nalbandy
Dept. of Chemistry and Biochemistry, California State University, Fullerton, Fullerton, California 92634
ABSTRACT: Secondary alcohols are rapidly oxidized to ketones by a solution of TCCA in acetone.
Ketones are often synthesized by the oxidation of secondary alcohols. We wish to report a fast, simple procedure for the synthesis of ketones from secondary alcohols which is suitable for moderate to large scale reactions. (ning sez: huh huh huh)
Trichloroisocyanuric acid [1] is a relatively stable and inexpensive reagent which has been used synthetically for the chlorination and oxidation of various types of compounds .(1) Secondary alcohols are rapidly converted into ketones with a solution of 1 in acetone containing pyridine.(2) The ketone products are isolated by extraction after removing the cyanuric acid [2] by filtration and replacing the acetone with ether. The yields and purities for the distilled or recrystallized products are shown in the table.
R1 R1
\ \
3 CHOH + TCCA + 3 Pyr ---> 3 C=O + Cyanuric acid + 3 Pyr.HCl
/ /
R2 R2
Secondary alcohols are oxidized considerably faster than primary alcohols with TCCA allowing selective oxidation of secondary alcohols in the presence of primary alcohols. Selectivity is shown by the oxidation of 2-ethyl-1,3-hexanediol to 2-ethyl-1-hydroxy-3-hexanone, the last entry in the table; none of the starting diol remained in the distilled product. Selectivity is also shown by a competitive experiment using 3.52 mmol 3-heptanol, 3.55 mmol 1-nonanol, 5.19 mmol pyridine, and 1.66 mmol TCCA. Analysis by GC after a 4-minute reaction time showed that only 2% of the 3-heptanol remained compared to 88% of the 1-nonanol.
During the oxidation of secondary alcohols, HCl is formed, and HCl reacts with TCCA to give chlorine(3). This does not inhibit the oxidation, but since some of the chlorine escapes from the reaction mixture, the amount of oxidizing agent required to carry a reaction to completion becomes less clear. The addition of a slight excess of pyridine minimizes the formation of chlorine.
It has been reported that TCCA will chlorinate ketones (1,5), but this unwanted side reaction can be reduced by several methods. The use of acetone as the reaction solvent limits the amount of chlorination of the ketone product.(6) The oxidation also proceeds well in acetonitrile, but a higher ratio of chloro ketone is produced. The oxidation proceeds rapidly without pyridine, but the extent of chlorination is less when pyridine is added. This is presumably because HCl promotes equilibration between the ketone and its enol, and it is the enol which is chlorinated(5). A lower ratio of TCCA to alcohol will give less chlorination because the concentration of TCCA remaining after the oxidation is complete will be less. Quenching the reaction with sodium hydrogen sulfite, which destroys TCCA, as soon as the oxidation is complete will minimize chlorination as well. Since chloro ketones are quite reactive toward nucleophiles, they are normally converted to hydroxy ketones during the sodium hydroxide wash step in the workup and are removed at either the extraction or distillation stage.
The low cost of TCCA, the speed of the reaction, and the ease of isolation of the products make TCCA the oxidizing agent of choice for the conversion of secondary alcohols to ketones.
Experimental:
Oxidation of 2-Octanol to 2-Octanone:
The following procedure is typical. In a 500 ml, three-neck, RB flask were placed 7.0 g (54 mmol) 2-octanol, 6.2 ml (77mmol) pyridine, 40 ml acetone, and a stir bar. The flask was fitted with a condensor, dropping funnel, and stopper. In 50 ml acetone was dissolved 5.68 g (24.4 mmol, 73.2 meq) TCCA.(7) While stirring, the solution was added from the dropping funnel over a period of 1.5 min. The mixture was stirred for total of 20 min, then checked for the presence of TCCA using wet iodide-starch test paper. The test was negative (
, so the mixture was vacuum filtered to remove the cyanuric acid, and the filtrate concentrated using a rotary evaporator. Ether, 60 ml, was added and the solution washed with 1 N HCl (2x10 ml), 4 N NaOH (10 ml), and saturated salt solution (15 ml), dried over MgSO4, and vacuum filtered. After removal of the ether, the residue was vacuum distilled through a concentric tube column to give 5.73 g. (47.0 mmol, 83%) of 2-octanone: bp 95.0-97.0 C (42 torr)); 99% pure by GC analysis; the IR and NMR spectra agreed with spectra of the standard.
The reaction was carried out essentially the same way on a larger scale starting with 50.3 g (386 mmol) 2-octanol, 50.0 ml (620 mmol) pyridine in 250 ml acetone and 49.6 g (213 mmol) TCCA in 400 ml acetone added over a period of 60 min with 15 min additional reaction time. Distillation of the 2-octanone gave 40.6 g (317 mmol, 83%) with a bp of 77.8-80.0 C and a purity of 95% by GC.
The Table:
Oxidation of Secondary alcohols to ketones with TCCA
Alcohol Ketone Yield BP/torr Purity
-----------------------------------------------------------
3-heptanol 3-heptanone 85% 136.2/35 99%
2-octanol 2-octanone 83% 95.0 /42 99%
3-octanol 3-octanone 81% 73.6 /26 99%
cyclohexanol cyclohexanone 68% 58.0 /26 97%
2-me-cyclohexanol 2-me-" 77% 63.8 /24 99%
menthol menthone 82% 108.2/35 99%
borneol camphor 86% mp 174.8 99%
1-Ph-ethanol 1-Ph-ethanone 90% 107.0/39 99%
Ph-2-propanol Ph-2-propanone 85% 109.8/25 99%
2-Et-1,3-hexanediol "-1-HO-3-hexanone 72% 123.2/25 95%
Refs:
1. (a) Hiegel, et al, Synth. Comm., 1985, 15,5, 385
(b) Back et al, Can. J. Chem., 1991, 69,9, 1482
(c) Walters, et al, J. Org. Chem., 1991, 56, 316
2. A previous report of small scale (0.5 g or less) oxidation of several steroid and two terpene alcohols using TCCA has appeared: Mukawa, F., Nippon Kagaku Zasshi, 1957,78,450; Chem abst., 1959, 53, 5338a. This study was of limited scope and a general oxidation procedure was not developed.
3. Hiegel et al, J. Chem. Ed., 1987, 64, 2, 156
4. Stevens et al, J. Org. Chem., 1980, 45, 2030
5. (a) Radhakrishnamurti et al, Indian J. Chem., 1985, 24A, 300;
(b) Vasudevan et al, ibid, 304.
6. Acetone is also chlorinated, but the chloro compounds are effectively destroyed during workup.
7. As with other strong oxidizing agents, TCCA should be added to the solvent rather than the solvent being added to TCCA otherwise a violent reaction could occur. An excess of TCCA was used because some is lost due to side reactions, and it has been reported to be about 90% reactive as determined by a thiosulfate titration of the iodine liberated on reaction of TCCA with iodide. See Eaton, Mfg. Chemist and Aerosol News, 1964, 35, 12, 45.
8. If the test had been positive, then saturated NaHSO3 solution would have been added, and the solution stirred for a few minutes and tested again. This procedure would have been repeated until the test was negative.
