OXIMESOF HINDEREDKETONES
May 5, 1959 [CONTRIBUTION FROM THE
2151
MERCKSHARP & DOtrars RESEARCH LABORATORIES, DXWSION OF MERCK & CO., INC.]
High Pressure Studies : Oximes of Hindered Ketones B Y WILLIAMH. JONES,E. W. TRISTRAM AND WILLIAMF. BENNING RECEIVED OCTOBER13, 1958 Highly hindered, unreactive ketones react with hydroxylamine a t pressures of about 9500 atmospheres to give good yields of the corresponding oximes. Qualitative rate studies showed a marked positive effect of pressure on reaction rate which is interpreted to mean that the rate-determining step involves the formation of a highly polar activated complex from neutral or much less polar reactants.
Hydrostatic pressure may produce pronounced effects on the rate and course of liquid phase ‘ a:tions. For reactions which proceed by an ionic mechanism, a rationale for these effects was not evident until the recent work of Hamann’ who demonstrated that in polar media those “reactions in which the transition state is more highly ionic, and hence more extensively solvated, than the hitial state are greatly accelerated by pressure; those in which the transition state is less ionic and less solvated than the initial state are retarded by pressure.la’’ The positive pressure effect is caused by a binding of the solvent molecules to the more highly charged activated complex with a resulting decrease in the volume of the system. The basic relationship between pressure and rate was originally proposed by van? Hoff ( l y T = -R -TA V S
where, according to modern theory, AV* is the change in volume per mole when the activated complex is formed from the reactants. The effect of pressure on the equilibrium constant follows an analogous relationship. The effect of pressure on addition reactions of carbonyl compounds such as the formation of oximes, hydrazones, semicarbazones, etc., which are ionic reactions exhibiting general acid catalysis, has not been studied. It was hoped that the ratedetermining step might involve the formation of a charged complex, despite conflicting conclusions in the l i t e r a t ~ r e ~on- ~this point, and therefore the reactions might be accelerated by pressure. Also since certain oximes would provide a convenient route to some desired amines, we have investigated the reaction of several hindered ketones with hydroxylamine. Di-t-butyl ketone (hexamethylacetone) (I) is a classic example of a sterically hindered carbonyl compound uncomplicated by other functional groups or extraneous electrical effects. Although (1) (a) J. Buchanan and S. D. Hamann, Trans. Faraday Soc.. 49, 1425 (1953); (b) H. C. David and S. D. Hamann, ibid., 60, 1188 (1954); (c) S. D. Hamarm and W. Strauss, ibid., 61, 1684 (1955); (d) H. G. David, S. D. Hamann and S. J. Lake, A usfralion J . Chctn.. 8, 285 (1055); (e) S. D. Hamann. “Physico-Chemical EEects of Pressure,” Academic Press, Inc.. New York, N. Y., 1957. (2) van’t HOE, “Vorlesungen uber theorstische und physikalische Chemie,” Vol. I , Bratinschweig, 1901. p. 236. (3) J. Hine, “Physical Organic Chemistry,” McCraw-Hill Book Co., Inc., N e w York, N . Y..1956, pp. 246-251. (4) P. D. Bartlett. Chapter 1 in H. Giman’s, “Organic Chemistry,” Vol. 111, John Wilep and Sons, Inc., New York, N. Y., 1953. pp. 117118. (5) L. P. Hammett, “Physical Organic Chemistry,” McGraw-Hill Book Co., Inc., New York, N. Y., 1940, pp. 330-336. (6) C. €1. Stempel, Jr., and G. S. Schaflel, THIS JOURNAL, 66, 1150 (1944): R. P. Cross and P. Fugassi, ibid., 71, 223 (1949).
this ketone will undergo addition reactions with a few small molecules like methyl Grignard reagent and hydrogen, the common carbonyl derivatives have never been prepared despite repeated attempts t o do SO? When hexamethylacetone was treated with hydroxylamine a t a pressure of about 140,000 p.s.i., however, a 70% yield of pure crystalline oxime was obtained. As expected, the less hindered pentamethylacetone (11) was even more reactive under the same conditions, giving a 96% yield of oxime in a shorter time. Catalytic reduction of hexamethylacetone oxime in good gave 2,2,4,4-tetramethyl-3-aminopentane yield, This amine possessed a high order of activity in a ganglionic blocking assay. 11-Ketosteroids also possess a very unreactive carbonyl group. Attempts t o prepare an oxime (IV) from 3,2O-bis-ethylenedioxy-5-pregnene-l7a, 21-diol-11-one (cortisone-3,20-bis-dioxolane) (111) by standard procedures a t atmospheric pressure gave poor yields of oxime in difficultly-separable CH,OH
CHiOH
c:L IV
mixtures. Low solubility of the steroid made it necessary to employ a complex solvent mixture of ethanol, water and pyridine. With this mixture and using an additional buffer of sodium acetate, it was possible to obtain a 74% yield of crystalline oxime by operating a t 134,000 p.s.i. pressure. In order to obtain a clearer picture of the effect of pressure on these reactions, qualitative rate studies were made. The results of the kinetic experiments are presented in Tables I and I1 and in Fig. 1. Experimental8 High Pressure Apparatus.-The 12H Series equipment of the Harwood Engineering Co. was used for all high pressure experiments. The reactor, designed for operation to 200,000 p.s.i., had the following dimensions: 8” 0.d. X 30” long, void space 1” i.d. X 12” long. It was fitted with conventional Bridgman closures a t both ends. Pressures were generated with an U . 5 J pressure intensifier driven by (7) A. Haller and E. Bauer, Compf. rend.. 160, 582 (1910); Bruzau, Ann. chim., [ll] 1, 257 (1934); J. B. Conant and A. H. Blatt, THIS JOURNAL, 61, 1235 (1929); N. C. Cook and W. C. Percival. ibid., 71, 4141 (1049); F. C. Whitmore, “Organic Chemistry,’’ D. Van Nostrend Co., Inc.. New York, N . Y., 1951, p. 223. (8) All melting and boiling points arc oncorrected.
Vol. 81 'rAllLE
RArE
OF
11
FORMATION 0 1 2 HEXA?IZETHYLACE.IOX~ Osi\ii; AT 75
Solvent: ethanol-water in 1.3: 1 proportion by weight; concentrations: hydroxylaminc hydrochloride, 0.17 molal; sodium acetate, 0.23 molal. Initial molal concn. of ketone
0.x
t-
/
>
d
:L20,000 p.s.i. Milton Roy pump, and measured with a man-
w n i n cell using a special Foxboro Null Balance Indicator, a n A C bridge designed for use with the cell and calibrated prcssure units. Iicaction mixtures were confined in a collapsible sample holder fabricated from a stainless steel bellows (Flexonics Corporation, Maywood, Ill.), 0.75" 0.d. X 11.5" long, which was closed at both ends with brass screw caps containing flat Teflon gaskets. T h e sample holder was placed inside a closely fitting thin-walled stainless steel tube which permitted linear compression while preventing kinking of the bellows. This entire assembly was then immersed in the reactor, il lead-free gasoline (dnioco) serving as the hydraulic fluid. T h e capacity of the sample holder was approximately BO ml. ill
TAI
