[www.rhodium.ws] [] [Chemistry Archive]
 
 

Sodium Hypochlorite Oxidation of
Secondary Alcohols to Ketones

R.V. Stevens, K.T. Chapman, H.N. Weller
J. Org. Chem. 45, 2030-2032 (1980)

HTML by Rhodium

In connection with certain studies concerned with the total synthesis of chirally pure natural products,1 we required large quantities of (-)-camphor. This substance can be obtained from relatively inexpensive (-)-borneol by oxidation with an almost bewildering array of reagents.2 However, the need for repeated large-scale work forced us to consider factors such as cost, ease of operation, and total reaction volume in the selection of an oxidation procedure. In our previous work1 we had employed tert-butyl hypochlorite. However, the somewhat tedious preparation3 of this reagent and its potentially explosive nature,3 especially during large-scale preparations, led us to consider alternate sources of positive chlorine which might effect the same transformation. Sodium hypochlorite has been used indirectly with ruthenium tetroxide to oxidize secondary alcohols to ketones;4 reportedly, no reaction occurs in the absence of catalyst. Sodium hypochlorite has also been used in a two-phase system with a phase-transfer catalyst to oxidize secondary alcohols to ketones in moderate yield.5 In our hands this procedure failed to oxidize borneol to camphor and led to a complex mixture of polymeric products.

Table I.
Oxidation of Alcohols with NaOCl

Entry
Alcohol Product
Yield*
1
(-)-borneol(-)-camphor
95%
2
(±)-isoborneol(±)-camphor
91%
3
(-)-menthol(-)-menthone
94%
4
cyclohexanolcyclohexanone
96%
5
2,2,5-trimethylcyclohexanol2,2,5-trimethyl-
cyclohexanone
90%
6
9-cyanoisoborneol9-cyanocamphor
94%
7
5α-androstane-3β,17β-diol 5α-androstane-
3,17-dione
96%
8
norborneolnorcamphor
92%
9
2-octanol2-octanone
96%
10
1-decyl alcoholdecyl decanoate
89%
11
2-ethyl-1,3-hexanediol2-ethyl-1-hydroxy-
3-hexanone
85%

* Yields represent isolated, pure products. Known products
identified by comparison with authentic samples. New ones
were characterized by their 1H,13C NMR, IR, and MS spectra.

We now report that secondary alcohols are cleanly oxidized to ketones with sodium hypochlorite in acetic acid in the absence of catalyst. Inexpensive concentrated solutions of sodium hypochlorite are sold commercially as "swimming pool chlorine"6. Dropwise addition of this reagent to a solution of the alcohol in acetic acid at room temperature leads to an exothermic reaction which is usually complete 15 min after the end of the addition. Ketones are isolated in excellent yield (see Table I) by diluting the mixture with water and collecting the products by filtration (solids) or extraction (liquids). We have repeatedly used this procedure for the oxidation of borneol to camphor without incident.8

Other secondary alcohols are oxidized equally efficiently (see Table I). The reaction appears to be relatively insensitive to geometric or steric constraints (e.g., compare Table I, entries 1 and 2, 4 and 5). Methyl ketones are formed without undergoing a subsequent haloform reaction (entry 9). Primary aliphatic alcohols react sluggishly, leading to dimeric esters, presumably via hemiacetal intermediates (entry 10).9 We have made use of this difference in reactivity to oxidize a secondary alcohol in the presence of a primary alcohol (entry 11). The use of this reagent as a selective oxidant and applications of the ester-forming reaction will be the subject of a future paper.

Experimental

General Procedures

Sodium hypochlorite solutions6 and glacial acetic acid (Mallinckrodt, analytical reagent) were used as received. Starting alcohols were purified by distillation or crystallization, as appropriate; purity was established by vapor-phase or thin-layer chromatography prior to use.

Oxidation of (-)-Borneol

(-)-Borneol (502 g, 3.26 mol, [α]25D (CHCl3) -35.3°) was dissolved in glacial acetic acid (1.5 L) in a 5-L 3-neck flask fitted with a mechanical-stirring apparatus and thermometer. Aqueous sodium hypochlorite solution (2 L of 2.0 M solution, 4.0 mol) was added dropwise over 2.5 h. The mixture was cooled in an ice bath as necessary to keep the internal temperature in the range 15-25°C. The mixture was stirred for 1 h after completion of the addition, at which time a positive potassium iodide-starch test was obtained. Saturated aqueous sodium bisulfite solution (200 mL) was added until the color of the mixture changed from yellow to white and the potassium iodide-starch test was negative. The mixture was then poured over an ice-brine mixture (10 L), and the resulting white solid was collected on a Buchner funnel and washed with saturated aqueous sodium carbonate solution until foaming was no longer evident. The solid product was pressed as dry as possible and dissolved in petroleum ether (2 L, bp 20-60°C), and the aqueous and organic layers were separated. The aqueous layer was extracted twice with petroleum ether and discarded. The organic layers were combined and dried over anhydrous calcium chloride. The mixture was concentrated by rotary evaporation until most of the petroleum ether was removed and a white slurry remained. The remainder of the petroleum ether was then removed by high-vacuum rotary evaporation with the condenser cooled to -78°C to prevent sublimation of camphor, leaving 475 g (95.8%) of (-)-camphor as a free-flowing white powder, mp 175.5-176.5°C, [α]25D (CHCl3) -42.1°.

Oxidation of Cyclohexanol

Cyclohexanol (99.0 g, 0.988 mol) was dissolved in glacial acetic acid (660 mL) in a 2-L 3-neck flask fitted with a mechanical-stirring apparatus and thermometer. Aqueous sodium hypochlorite (660 mL of 1.80 M solution, 1.19 mol) was added dropwise over 1 h. The reaction was cooled in an ice bath to maintain the temperature in the 15-25°C range. The mixture was stirred for 1 h after the addition was complete. A potassium iodide-starch test was positive. Saturated aqueous sodium bisulfite solution (3 mL) was added until the color of the reaction mixture changed from yellow to white and the potassium iodide-starch test was negative. The mixture was then poured into an ice-brine mixture (2 L) and extracted six times with ether. The organic layer was washed with aqueous sodium hydroxide (5% by weight) until the aqueous layer was basic (pH test paper). The aqueous washes were then combined and extracted five times with ether. The ether layers were combined and dried over magnesium sulfate. The ether was distilled through a 30-in. Vigreux column until less than 300 mL of solution remained. The remainder was fractionally distilled through a 12-in. Vigreux column. After a forerun of ether, cyclohexanone (bp 155°C) was distilled to give 92.9 g (95.8%) of a colorless liquid, identical with an authentic sample.

Oxidation of 2-Ethyl-1,3-hexanediol

2-Ethyl-1,3-hexanediol (Eastman, 10.12 g, 0.068 mol) was dissolved in glacial acetic acid (50 mL) in a 250-mL 3-neck flask equipped with a thermometer and magnetic stirring bar. Aqueous sodium hypochlorite (49 mL of 1.48 M solution, 0.072 mol) was added dropwise over 1 h. The reaction was cooled in an ice-water bath as necessary to maintain the temperature between 20 and 25 °C. The mixture was stirred for 30 min after completion of the addition, after which a potassium iodide-starch test was negative. The reaction mixture was poured into ice-brine (300 mL), and the resulting mixture was extracted five times with ether. The combined ether extract was washed three times with saturated aqueous sodium carbonate solution and twice with aqueous sodium hydroxide solution (5% by weight). The aqueous washes were combined and extracted three times with ether. The ether extracts were then combined, dried over anhydrous magnesium sulfate, and concentrated by rotary evaporation to give a colorless oil (9.64 g). Vacuum distillation in a short-path apparatus gave 8.42 g (85%) of 2-ethyl-1-hydroxy-3-hexanone as a colorless oil10.

References

  1. R. V. Stevens and F. C. A. Gaeta, J. Am. Chem. Soc., 99, 6105 (1977)
  2. For leading references, see "Compendium of Organic Synthetic Methods", (I. T. Harrison and S. Harrison, Vol. I and II; L. G. Wade, Vol. III), Wiley-Interscience, New York.
  3.  
    1. Preparation:
      Organic Syntheses, Coll. Vol. 4, p. 125 (1963) Wiley, New York
      Organic Syntheses, Coll. Vol. 5, p. 184 (1973) Wiley, New York
    2. Use as an oxidant:
      C. A. Grob and H. J. Schmid, Helv. Chim. Acta, 36, 1763 (1953)
      D. Ginsburg, J. Am. Chem. Soc., 75, 5489 (1953)
      G. S. Fonken, J. L. Thompson and R. H. Levin, J. Am. Chem. Soc., 77, 172 (1955)
  4. S. Wolfe, S. K. Hasan, and J. R. Campbell, J. Chem. Soc. D, 1420 (1970)
  5. G. A. Lee and H. H. Freedman, Tet. Lett., 1041 (1976); S. L. Regen, J. Org. Chem., 42, 875 (1977)
  6. We used Sani-Chlor Pool Sanitizer (General Pool Supply, Los Angeles, CA 90045) which is sold as a 12.5% solution by weight. As sold, these solutions were found to be 1.8-2.0 M by means of a simple titration procedure.7 On standing at room temperature in their original containers, these solutions decreased in concentration by about 20% per month. For most applications an excess of the reagent can be used with the stated concentration as a guide. For more precise work the simple titration procedure7 is recommended. Our cost was $0.95/gal or about $0.13/mol.
  7. I. M. Kolthoff and R. Belcher, "Volumetric Analysis", Interscience, New York, 1957, pp 262-6.
  8. We have experienced no difficulties in working with this reagent. However, as with all strong oxidants, care should be taken due to the potential for formation of peroxides.
  9.  
    1. Preparation of esters from aldehydes via hemiacetals has been described previously:
      P. Sundararaman, E. C. Walker, and C. Djerassi, Tetrahedron Lett., 1627 (1978)
    2. Oxidation of primary benzylic alcohols by hypochlorites has been described previously:
      C. Y. Meyers, J. Org. Chem., 26, 1046 (1961)
  10. I. I. Lapkin and F. G. Saitkulova, Zh. Org. Khim., 6, 450, (1970)