Ind. Eng. Chem. Res. 2000, 39, 1119-1123
1119
APPLIED CHEMISTRY Multiple-Batch, Wolff-Kishner Reduction Based on Azeotropic Distillation Using Diethylene Glycol Edmund J. Eisenbraun,* Kirk W. Payne, and Jeremy S. Bymaster Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078
The Huang-Minlon (Wolff-Kishner) procedure for deoxygenating aldehydes and ketones is improved by recycling excess hydrazine hydrate instead of distilling to increase the reaction temperature. This procedural change provides lower reaction and distillation temperatures and a short reaction time. It is applicable to those examples which are compatible with a refluxing mixture of diethylene glycol, hydrazine hydrate, and alkali and yield a product forming an azeotropic bilayer with diethylene glycol and hydrazine hydrate. The apparatus essential to these operational changes is described. Multibatch runs reusing reagents (alkali, diethylene glycol, and some retained hydrazine hydrate) show that high yields and product purity remain unchanged throughout this repetitive process and that accumulation of nonvolatile residue is minimal over a series of multiple runs applied to 2′-acetonaphthone and dimethoxybenzaldehydes. This suggests that a continuous process, utilizing these techniques, could be developed. The Wolff-Kishner reduction has been extensively used for deoxygenating aldehyde and ketone functions to methyl and methylene. The use of glycols to increase the reaction temperature was introduced by Whitmore1 and further studied by Soffer.2 Huang-Minlon3 substituted hydrazine hydrate (safer and less expensive) for anhydrous hydrazine, sodium hydroxide for metallic sodium, and increased the reaction temperature (190200 °C) in diethylene glycol (DEG) by driving off water and excess hydrazine hydrate to complete the reaction. Since 1967 over 33% of the 1068 Wolff-Kishner references cite the Huang-Minlon modification. Hutchins and Hutchins4 recently reported other modifications, involving changes of solvent and reaction conditions, which expanded the scope and yield of the reaction. Earlier reviews of the Wolff-Kishner reduction include those by Todd,5 Fieser and Fieser,6 and Reusch.7 The latter reference provides helpful information for selecting a reduction method. Sodium cyanoborohydride, which has greater selectivity under milder reaction conditions, has been cited as a popular substitute for the Huang-Minlon method.4,8-10 A recent reviewer11 has categorized the Wolff-Kishner reduction as rarely employed because of the less harsh conditions of recently developed sequences. This raises the question of the suitability and future role of the Wolff-Kishner reduction. If sodium cyanoborohydride is to replace the Wolff-Kishner reduction, several points must be considered, particularly in preparative work: formation of hydrogen cyanide, disposal of toxic reagents and solvents, and reagent costs. Low reagent cost, the fact that hydrazine is consumed during the reaction, and the ease with which excess hydrazine is destroyed by * To whom correspondence should be addressed. Phone: (405) 744-6673. Fax: (405) 744-6007. E-mail: eisenbr_osu@ osu.net.
Scheme 1
bleach12,13 or hydrogen peroxide13 recommend continued use of the Wolff-Kishner reduction. Our experience with the Wolff-Kishner reaction was gained through numerous syntheses of multimole quantities of rigorously pure organic compounds for use in thermodynamic studies as part of the American Petroleum Institute Research Projects during 1962-1974 and subsequent sponsorship by the U. S. Department of Energy. These syntheses frequently involved trial and comparison of the various routes for deoxygenating aldehydes and ketones. Initially, the Clemmensen reduction and catalytic hydrogenolysis were used. However, pinacol formation with acid-catalyzed rearrangement in the Clemmensen reduction5,14 and catalytic overhydrogenation,5 resulting in reduction of aromatic rings, eventually caused a shift of preference to the more reliable Wolff-Kishner reduction which is free of these side reactions. In this paper, to reinforce the utility of the Wolff-Kishner reduction, we demonstrate that reductions can be carried out at lower temperatures (100-150 °C) and shorter reaction times (99% purity). After the reaction vessel is flushed with argon for 5 min, the argon flow is cut off and rapid magnetic stirring is started. The reactor temperature rises ≈10 °C. Heating is begun and the reactor temperature is rapidly brought to 100 °C in 1015 min. Slow initial heating may lead to azine formation (Scheme 1), seen as a yellow froth. Nitrogen from the reaction begins to evolve between 60 and 70 °C and becomes very rapid as the temperature rises to 130150 °C (reactor temperature) in 15-30 min. The heating rate is maintained until the vigorous nitrogen evolution diminishes (≈40 min), and heating is then increased to provide distillation. Argon flow is resumed as needed to prevent backup. The product begins to appear as an upper layer in the Dean-Stark apparatus (≈25 min.). The lower layer (water/hydrazine hydrate/DEG) is drained from collection chamber C and reflux is continued until the distillation temperature rises above 105 °C. Thereafter, the distillate is recycled to the reaction flask, and as the product layer collects, it is periodically (usually 5-min intervals) drained into a 250-mL graduated cylinder. The reaction vessel temperature gradually increases as the azeotrope layer is removed. The process is continued until no more product layer is produced. The collected material is diluted to 250 mL with water, which then gives 94-99 mL of product layer. This quantity varies with different starting materials. A 4050 mL replenishment supply of DEG was added for each run. The supply of hydrazine hydrate and aldehyde was replenished as well, and seven succeeding runs were carried out in the same manner as the initial run. The collected fractions from all runs were added to a 2-L separatory funnel and the layers were separated. The water layer was extracted with 2 × 500 mL of hexane and the extract was washed with water, 1/10 hydrochloric acid/water, and brine. The hexane extract and the product layer were combined, spray washed with water, 1/10 hydrochloric acid/water, brine, saturated aqueous bicarbonate, dried (MgS04), filtered, concentrated, and distilled at 120 °C/3 mm to give 744 g (94% overall yield) of 3,5-dimethoxytoluene. Gas chromatography studies were done as follows: the product from each run was sampled, diluted with hexane, freed of hydrazine by passing through a short plug of acidic alumina, and then analyzed by GC using a 15 m × 0.25 mm, J&W BD-5ms capillary column. These studies showed the product purity (>99%) did not change during the individual runs. Final distillation purity was 99.7%. Gas evolution is useful to monitor the progress of the reaction. However, bubbling as a result of expansion during heating, particularly as the boiling point of water and/or hydrazine hydrate (≈120 °C) is approached, can be misleading. Application of the Wolff-Kishner Procedure to Other Examples The above procedure, essentially without modification, was used to convert 937 g (5.64 mol) of 2,4dimethoxybenzaldehyde to 815 g (95% yield) of distilled
2,4-dimethoxytoluene, showing >99% purity in 13 runs. The above procedure also was used to convert 2′acetonaphthone to 2-ethylnaphthalene. Ten runs using 851 g (5.0 mol) of purified 2′-acetonaphthone, recrystallized to >99.6% purity from 2-propanol, gave 765 g (98% yield) of distilled 2-ethylnaphthalene showing >99 purity. The data resulting from temperature change and other parameters, as the reaction proceeded, were used to construct the distillation curves of Figures 4 and 5. The contents of the reactor, after the final run, were found to be a nearly colorless liquid which upon dilution with water, acidification, and extraction with ether gave 1.6 g (0.6% yield calculated as dimeric aldol product) of light tan solid showing broad mp (molten at 105 °C). Concerns about Side Reactions Harsh reaction conditions, principally hot alkali in the presence of water and a protic solvent at high temperature, is a major criticism of the Wolff-Kishner reduction. In selecting the starting materials for this study, methoxy group cleavage to phenolic products and aldol condensation of the acetyl group were considered possible. These reactions could lead to reduction in yield but not influence the purity of the product because these side products remain in the reaction vessel. The high yield and purity of product in each case show that these and other side reactions are minimal. Suggestions for Waste Disposal and Safety Measures Hydrazine is extremely toxic and should be kept in a hood at all times. Appropriate gloves and face shield are needed during manipulation. It is quickly and effectively destroyed by commercial bleach (5.25%) which should be kept on hand to destroy spilled and waste material.12 Water and acid washings from extractions containing hydrazine are made alkaline and treated with an excess of bleach before being disposed to the sewer.12,13 A practical procedure for disposal of hydrazine consists of adding 10 mL of hydrazine hydrate to a 4-L beaker containing a magnetic stirring bar and 1 L of cracked ice. Bleach (500 mL) is cautiously added (foaming). An additional 250 mL is added; the beaker contents are allowed to stand overnight and are neutralized before being discarded to the sewer.13 The DEG drained from the reaction vessel may be distilled at reduced pressure for reuse or disposed as burnable waste. CAUTION: hydrazine is likely present. The DEG distillation residue, containing alkali, is diluted, checked, and treated for hydrazine with bleach and neutralized for disposal. Conclusions The described apparatus and procedure permit effective isolation of product with a minimal amount of high boiling residue. An excess of recycling hydrazine hydrate, during Wolff-Kishner reduction of 2′-acetonaphthone and dimethoxybenzaldehydes, effectively lowers the reaction and azeotropic-distillation temperatures. Reusing potassium hydroxide as well as a major portion of DEG, during multibatch runs, provides a substantial decrease in reagent consumption while excellent yields and high product purity are maintained. These effects and benefits suggest that the described apparatus and the azeotropic-distillation procedure could be developed
Ind. Eng. Chem. Res., Vol. 39, No. 5, 2000 1123
into a continuous commercial process while minimizing reagent cost, reaction time, and waste disposal. Literature Cited (1) Herr, C. H.; Whitmore, F. C.; Schiessler, R. W. The WolffKishner Reaction at Atmospheric Pressure. J. Am. Chem. Soc. 1945, 67, 2061. (2) Soffer, M. D.; Soffer, M. B.; Sherk, K. W. A Low-Pressure Method for Wolff-Kishner Reduction. J. Am. Chem. Soc. 1945, 67, 1435. (3) Huang-Minlon. A Simple Modification of the Wolff-Kishner Reduction. J. Am. Chem. Soc. 1946, 68, 2487. (4) Hutchins, R. O.; Hutchins, M. K. Comprehensive Organic Synthesis. In Reduction of C)X to CH2 by Wolff-Kishner and other Hydrazone Methods; Trost, B. M., Fleming, I., Eds.; Pergamon: New York; 1991; Vol. 8, pp 327-362. (5) Todd, D. Organic Reactions. In The Wolff-Kishner Reduction; Adams, R., Ed.; John Wiley & Sons: New York, 1948; pp 378422. (6) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John Wiley & Sons: New York, 1948; pp 435-445 (Also see later volumes of this series). (7) Reusch, W. Reduction. In Deoxygenation of Carbonyl Compounds; Augustine, R. L., Ed.; Dekker: New York, 1968; pp 171211. (8) Hutchins, R. O.; Maryanoff, B. E.; Milewski, C. A. Selective Reduction of Aliphatic Ketones and Aldehydes to Hydrocarbons with Sodium Cyanoborohydride and p-Toluenesulfonyl Hydrazide in Dimethylformamide-Sulfolane. J. Am. Chem. Soc. 1971, 93, 1793. (9) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. Selective Deoxygenation of Ketones and Aldehydes Including Hindered Systems with Sodium Cyanoborohydride. J. Am. Chem. Soc. 1973, 95, 3662.
(10) Lane, C. F. Sodium CyanoborohydridesA Highly Selective Reducing Agent for Organic Functional Groups. Synthesis 1975, 135. (11) Whitesell, J. K. Comprehensive Organic Synthesis. In Carbonyl Group Derivatization; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 6, pp 703-732. (12) Armour, M. A. Hazardous Laboratory Chemicals Disposal Guide; CRC Press: Boca Raton, FL, 1991; pp 170-171. (13) Speer, S. E.; Pasricha, A.; Quinn, R. F. Automatic Monitoring and Treatment of Hydrazine. Ind. Water Treatment 1995, March/April, 48. (14) Duncan, W. P.; Russell, J. E.; Eisenbraun, E. J.; Keen, G. W.; Flanagan, P. W.; Hamming, M. C. The Clemmensen Reduction of 2-Acetonaphthone. J. Org. Chem. 1972, 37, 142. (15) Eisenbraun, E. J.; Hall, H. A Convenient Stainless Steel Vessel for Laboratory-Scale Alkaline Reaction Mixtures. Chem. Ind. (London) 1970, 1535. (16) Lane, R. K.; Adkins, M. W.; Hall, H.; Eisenbraun, E. J. Improved Reflux Condensers for Organic Chemistry Laboratories. J. Chem. Educ. 1986, 63, 995. (17) Cowan, K. D.; Bymaster, D. L.; Hall, H.; Eisenbraun, E. J. A Magnetically-Stirred, Variable-Temperature Catalytic Hydrogenation Apparatus. Chem. Ind (London) 1986, 105. (18) Eisenbraun, E. J.; Hall, H. Inexpensive Steel Reaction Vessels and Accessories for Organic Reactions. Org. Prep. Proced. Int. 1972, 4, 19. (19) Horsley, L. H. Azeotropic Data-III; Gould, R. F., Ed.; Advances in Chemistry Series 116; American Chemical Society: Washington, DC, 1973; pp 257-260.
Received for review September 7, 1999 Revised manuscript received December 13, 1999 Accepted March 6, 2000 IE990670H
