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NORMAN H. CROAIWVELI., RANDALL P. AYERA N D PETERW-.FOSTER
1701.
s2
[CONTRIBUTION FRDM AVERY LABORATORY, UNIVERSITYOF NEBRASKA AND DEPARTMENT OF CHEMISTRY, UNIVERSITY COLLEGE, LONDON]
Elimination Reactions of a-Halogenated Ketones. I. Dehydrobromination of 2-B enzyl-2- bromo-4,4- dimethyl- 1-t etralone BY NORMAN H. CROMWELL, RANDALL P. AYERAND PETER W. FOSTER RECEIVED MAY14, 1959 2-I3enzyl-2-brorno-4,4-dimethyl-l-tetralone (I) has been found to undergo dehydrobromination to produce mainly the endocyclic a,B-unsaturated ketone, 2-benzyl-4,4-dimethyl-l-keto-1,4-dihydronaphthalene (11) employing various bases, water, iodide ions or silver ions. It is suggested t h a t the ionization of the axial or-bromine in I is assisted by steric facilitation and by the electrons of the axial CB-H bond. The thermodynamic stability of the endocyclic a,p-unsaturated ketone 11, relative to the isomeric exocyclic a,p-unsaturated ketone, 2-benzal-4,4-dimethyl-l-tetralone (HI), is suggested by the rearrangement of the latter (111) to the former (11) on heating with palladium.
In a previous publication' the facile dehydro- tetralone (IV) indentical with the ketone prebromination of 2-benzyl-2-bromo-4,4-dimethyl-1-viously prepared3 by the hydrogenation of the uiitetralone (I) with amines a t room temperature was saturated ketones I1 and 111. reported to produce mainly the endocyclic CY,@Ck!, \ / ('lid C'i1 , ,CII, unsaturated ketone, 2-benzyl-4,4-dimethyl-l-keto1,4-dihydronaphthalcne (11), along with smaller amounts of the exocyclic isomer, 2-benzal-4,4dimethyl-1-tetralone (111). The present article reports on some product studies of the reactions of various other types of bases and of silver nitrate with this cyclic cyhaloketone 1. Indications are that, in general, the bromoketone I produces mainly, if not exclusively, the endocyclic a,@-unsaturated ketone I1 under ordinary, and some not so ordinary, conditions of dehydrobromination. rv I11 Both potassium hydroxide and sodium methoxide Silver nitrate in ethanol was found to be a very were found to react readily a t room temperature with the bromoketone I to produce the endo- effective reagent for dehydrobrominating ketone I cyclic unsaturated ketone I1 in 67 and 82.5% to the unsaturated ketone 11. No indication of the yields, respectively (amounts isolated, not neces- presence of the isomeric exocyclic a,@-unsaturated sarily the total amounts actually present). Am- ketone 111 in the reaction mixture was observed monia in ethanol was found to react much more although small amounts may have been present. It was important to establish that the rearrangeslowly than the amines previously used'; ;.e., a 42y0 yield of ammonium bromide was produced ment of the unsaturated ketone I11 to 11, or vice versa, was not to be expected under the conditions oiily after six days a t room temperature. The bromoketone I undergoes a solvolysis re- employed for the dehydrobromination studies. action in aqueous dioxane to give a 20% yield of There was no indication of rearrangement of either the unsaturated ketone I1 after nine hours of heat- I1 or 111even after heating with sodium methoxide ing under reflux. Infrared studies with a residual and methanol or sodium amide in benzene. Reoil indicated some 2 - hydroxy - 2 -benzyl - 4,4 - di- arrangement of I11 to I1 also is not readily acmethyl-1-tetralone may also have been formed. complished with acids.$ The exocyclic a,@-unsaturatedketone 111 was Hcating the brotnoketone with dry spectrograde dioxane for the same length of time gave no ap- successfully rearranged to the endocyclic CY,@unsaturated isomer I1 by boiling with palladiumparent change. Even iodide ion in dry acetone a t reflux teinpera- on-charcoal in ethylene glycol. This result initure is apparently capable of bringing about some plies that t.he endocyclic isomer I1 is thermodydeliydrobrorniiiation of I to produce the endo- namicaIly more stable with respect to 111, and fits cyclic a,fl-unsaturated ketone 11. This was indi- the empirical generalization of Brown.6 It is also cated by an cxainination of the infrared spectrum interesting to observe that the infrared carbonyl of the product isolated after refluxing a sample of stretching vibration3 for the endocyclic CY$ketonc I with a dry acetone solution of potassium unsaturated ketone I1 a t 1662 c:n.-l iinplics that iodide for four hours.2 On the other hand, an this isomer is more nearly coplanar and conjugaacidified acetone-ethanol solution of potassium tion is more effective in polarizing the carbonyl iodide reacted normally with the bromoketone I to group, and in stabilizing the molecule in the ground give the saturated ketone, 2-benzyl-4,4-dimethyl-1- state than is the case for the exocyclic isomer 111, which has its carbonyl band a t 1673 ern.-'. (1) A. Hassner and N. H. Cromwell, THIS JOURNAL, 80, 901 (1958). Y
(2) A previous example of iodide ions bringing about a dehydrohalogenation with a cyclic a-halo ketone has been reported by G. Rosenkranz. 0. LIancera, J. Gatica and C. Djerassi, ibid., T P , 4077 (1950), who studied the reaction of 2,4-dibromo-3-ketoallosieroidis a n d fouod s m i e elimination ol hydrogen bromide took place which iiivolvcd the axial 4-bromine atom.
(3) A. Hassner and N. H. Cromwell, ibid., 80, 893 (1058). (4) N. J. Leonard and D. M. Locke, ibid., 11, 1852 (1965), found are readily isomerized t h a t l-methyl-3,5-dibenzylidine-4-piperidones by palladium in ethylene glycol to I-methyl-3.5-dibcnzyI-d-pyridones ( 5 ) H. C . Brown, J. IT. Brewster and H. Schectcr, i b i d . , 7 6 , 469 (lU6.1); H. C.Rrowii, J . P r g . ( ' h e m . , 22, 439 (19573.
Jan. 5, 1960
2-BENZl’L-2-BROM0-2,4-DIMETHYL-1 -TETRALONE
Neither the bromoketone I nor the parent saturated ketone IV was found to react with 2,4dinitrophenylhydrazine under the usual conditions. It seems probable that the normal carbonyl reactions with these ketones are somewhat sterically hindered. It has been reported that 2-bromo-ltetralone forms the 2,4-dinitrophenylhydra~one~ in the usual manner, but hydrogen bromide was not eliminated even under vigorous conditions with this reagent. Discussion of the Dehydrobrominations.-It is quite apparent that endocyclic elimination of hydrogen bromide from the 2-benzyl-2-bromo-ltetralones is the favored reaction under a rather wide variety of conditions. There are several factors associated with the stereochemical arrangements in these structures which suggest that this should be the case. First of all, as has been pointed out previously,’ the opportunity for a cyclic tran.r-2,3-diaxial loss of hydrogen bromide to produce the endocyclic alp-unsaturated ketone is undoubtedly an important facilitating factor, regardless of the mechanism of the reaction. The other factors are associated with the fact that the endocyclic a$-unsaturated ketone I1 appears to be the thermodynamically favored isomer, relative to 111. Saytzeff influences (conjugative effects) often control the orientation of elimination of HX from alkyl halides in both El and E2 rea c t i o n ~ . ~It is possible that the conjugation factors inherent in the incipient endocyclic CY$unsaturated ketone system favor the formation of its transition state. The opportunity for greater planarity in the endocyclic system may outweigh the factor of the exocyclic phenyl group and its potential ability to conjugate with the incipient exo double bond. I n considering the relative stabilities of endoand exo-cycloalkane double bond systems, Turner and Turne3 have drawn attention to the importance of variations in non-bonded interactions in a given pair of isomers. I n the a-haloketone I starting material there is the CH3-C4-CZ-Br (pseudo axial-axial) interaction, while in the nearly planar3 endocyclic a,O-unsaturated ketone I1 product the non-bonded interactions are expected to be less important. I n the exocyclic a,p-unsaturated ketone I11 the methyl groups a t Cq and the hydrogens a t C3 are probably nearly eclipsed and the exo phenyl group may interact with the C3methylene group. This non-bonded interaction factor may give an important steric facilitation to both the elimination reaction with I and the isomerization reaction with I11 to produce the stable endocyclic a,@-unsaturatedketone 11. The endocyclic isomer I1 appears t o be both thermodynamically and kinetically favored in these reactions. The silver-catalyzed elimination of hydrogen bromide from I is probably essentially a metal assisted El type reactione but might receive some (6) F. Ramirez and A. F. Kirby, THIS JOURNAL, 74, 4331 (1952). (7) C. K. Ingold, “Structure and Mechanisms in Organic Chemistry,’’ Cornell University Press, Ithaca, N . Y.,1953, p. 443. (8) R. B . Turner and R. H. Turner, TEIS JOURNAL,80, 1424 (1958). (9) See ref. 7, pp. 357-358, for a discussion of silver assisted SNI reactions.
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nucleophilic assistance from nucleophiles in the solution. The ease with which this silver reaction takes place a t room temperature gives a clear indication of the considerable ionic character of the bromine in this tertiary alicyclic a-haloketone I.l0 In addition to the steric facilitation suggested above i t is also possible that ionization of the bromine as Br- may be assisted by the electron H
I1
R’f
pair of the axial C r H bond.” It was found gives no that 2-brom0-4,4-dimethyl-l-tetralonel~~ reactionlZb with alcoholic silver nitrate under the comparable conditions used with the tertiary alicyclic a-haloketone I. It has also been found that the second-order reaction of this secondary alicyclic a-haloketone with piperidine in benzene to produce a mixture of the elimination product 4,4 - dimethyl - 1 - keto - 1,4 - dihydronaphthalene and the substitution product 4,4-dimethyl-2piperidino-1-tetralone is about one-eighth as fast as the comparable elimination reaction with ketone I.l-13 The conformational analysis of this secondary alicyclic a-bromoketone has clearly shown that i t possesses an equatorial bromine.a Thus C r H bond electron assistance for ionization of the a-bromine and a facile diaxial loss of hydrogen bromide in 2-bromo-4,4-dimethyl-l-tetralone is not expected to be as favored as in I. The factor of steric facilitation of ionization is probably also less with this secondary a-haloketone. A general discussion of some possible mechanisms for the base-catalyzed dehydrobrominations of I to I1 has been given previously.’ Kinetic studies13 of the dehydrobrornination of ketone I and some related cyclic a-bromoketones by amines in benzene, ethanol or acetonitrile solutions show these reactions to be essentially second-order reactions. Related studies now being undertaken with the B,b-dideuterio analog of I are expected to help in deciding between various possible bimolecular (Io) In general, primary acyclic a-haloketones react very slowly in ionization ( i . e . , SN1) reactions and this slowness of reaction has been ascribed to the destabilizing effect of the positive end of the C + = O dipole on the stability of the carbonium ion: see E. L. Eliel in M. S . Newman, “Steric Effects in Organic Chemistry,” John Wiley aud Sons, Inc.. New York. New York (1956), p . 103. (11) So-called hydrogen participation or CB-H bond electron assistance in bond breaking at the 0-carbon in cyclohexane derivatives is well discussed by D. J. Cram in the ref. cited in (10); see especially pages 270 and 327, and also see S. Winstein, et ai., TEIS JOURNAL, 74, 1127 (1952). (12) (a) R. T. Arnold, J. S. Buckley and 3. Richter. ibdd., 69, 2322 (1947); (b) N . H . Cromwell and P. H. Hess, ibid., 81, 136 (1959). (13) Unpublished work with Dr. Peter Foster, research associate, Uuiversity of Nebraska, 1957-1958. to be reported in detail elsewhere.
mechanisms for these base-catalyzed elimination reactions. Acknowledgment.-This work was supported in part by grant No. CY2931 from the National Cancer Institute, U. S. Public Health Service, and by the John Simon Guggenheim Memorial Foundation to whom the senior author is indebted for a fellowship in 1958. Experimental
(0.00262 mole) of the bromoketone I were refluxed it1 100 ml. of dry acetone for 4 hours in the absence of light. The red colored solution was evaporated uiider vacuum and t h e residur extracted with cther and the cthcr solutioii waslied with sodium thiosulfate and water. Coiiccritrztioii of thc ether solution prodiiced 0.55 g . of a pale yclloiv crystalline material, m.p. 65-73', which when rccrystallized once from methanol, m.p. 73-106", still gave a positive Beilstein test for halogen. The infrared spectrum, 15 mg./ml. CCl, in matched 1.O-mm. cells, showed two well resolved carbonyl bands, yC=O, sat. ketone, 1685 c111.-~/~37;yC=O, enclocyclic unsat. ketone, 1638 cn1.-'/9i. Heating the bromoketone I with dry acetone d o n e f,)r 7 The dehydrobromination studies were carried out with various reagents and pure 2-bronio-2-benzyl-4,4-dimethyl-l-hours produced no change. Potassium Iodide in Acidified Acetone-Ethanol .-A niixtetralone ( I ) , m.p. 101-102", prepared by the previously ture of a 0.5-g. (0.00146 mole) sample of the bromoketotie I , described method.3 Potassium Hydroxide in Ethanol.--9 5.0-g. (0.0146 mole) 0.48g. (0.00292 mole) of potassium iodide, 0.24 ml. (0.00140 mole of HCl) of 6 N hydrochloric acid, 16 ml. of dry acetone sample of the bromoketone I was dissolved in 800 ml. of abs. ethanol and 4.1 g. (0.73 mole) of potassium hydroxide in and 15 inl. of abs. ethanol \vas allowed t o stand a t room temperature. The red color of iodine developed immediately 150 ml. of abs. alcohol added at room temperature. After upon mixing the reagents. Aqueous sodium thiosulfate was standing in the dark at 25-28' for three days, neutralization added after 12 hours standing and the solution extracted with with acetic acid and concentration of the reaction mixture ether. From the ether solution was obtained 0.18 g. (40.Syo produced 2.55 g. (677, yield) of pure 2-benzyl-4,4-dimcthylyield) of 2 - b e n z y l - 4 , i - d i m e t h ~ l - l - t e t r a ~ ~(11'1, ne n1.p. I -keto-1,i-dihydronaphthalene (11), m.p. 113-114' . 3 Sodium Methoxide and Methanol.--% 5.0-g. (0.0146 60-62' . 3 Equilibration Studies with Unsaturated Ketones I1 and mole) amount of the bromoketone I was added t o a solution of 8.6 g. (0.073 mole) of sodium methoxide in 1.5 1. of abs. 111. ( a ) With Sodium Methoxide in Methanol.---\Vlieii either I1 or 1113was allowed t o stand at room temperature methanol. After standing at room temperature in the dark i i i the dark f o r 24 hours or refluxed for 4 hours with one inolar for three days the solution was neutralized with acetic acid equiv. of sodium uiethoxide in methanol, 90';:, of thc st:irting and concentrated t o produce 3.15 g. (82.57, yield) of the ketones was recovered. pure endocyclic unsaturated ketone II,3 m.p. 113-114'. ( b ) Sodium Amide in Benzene.--n'hen samples of S o evidence for the presence of 2-benzal-4,4-dimethyl-leither unsaturated ketone I1 or III were heated under reflus tetralone (111)was found. with finely ground sodium amide in benzene for 3.5 hours Ammonia in Ethanol.-A 0.5-g. (0.00146 molc) sample of the solutions developed a red color. T h e cooled solutions the bromoketone I was dissolved in 75 ml. of abs. ethanol were treated with methanol until the evolution of ammonia which was then saturated with anhydrous ammonia a t room ceased. Evaporation of the solvent and recrl-stallization of temperature. This reaction mixture was allowed t o stand the residues returned only the starting ketoiies in each case, a t room temperature for six days and concentrated t o pro6870 of I1 and 40% of 111. duce 0.06 g. (42Oj, yield) of ammonium bromide and 0.05 g. ( c ) Acetic Acid and HBr.--After heating R sample of t h e (137, yield) of the unsaturated ketone 11. Unchanged exocyclic unsaturated ketone I1 for 65 hours a t 5%70° with brornoketone I ( 0 . 1 7 g.) was also recovered. a glacial acetic acid solution saturate'd with HBr gas only Aqueous Dioxane.--A 2.0-g. sample of bromoketone I impure starting material was recovered as indicated by, m.p. was refluxed for 9 hours in 300 ml. of 5Oy0 aqueous dioxane. 108-110", mixed m.p. with ketone 111, 107-111°, and the inEvaporation of the solvent and crystallization of the residual frared spectrum, rC=O in CCla, 1673 ~ m . - ~ . ~ oil from methanol gave 0.29 g. (19% yield, not maximum ( d ) .Rearrangement of Ketone I11 to Ketone I1 with obtainable) of thg pure endocyclic cr,P-unsaturated ketone Palladium.--A 1.O-g. sample of the exocyclic unsaturated 11, m.p. 112-113 . The residual oil had an infrared spectrum in CClr indicating the possible presence of the starting ketone III3 was boiled with 0.1 g. of 10% palladium-oiicharcoal in 10 ml. of ethylene glycol for 40 minutes. The ketone I , the unsaturated ketone I1 and a hydroxyketone, catalyst was removed by filtration and the reaction mixture possibly 2-hydroxy-2-benzyl-4,4-dimethyl-l-tetralone; y O_H, 3600 cm.-'/20; yassoc. OH, 3200 cm.-'/45; yC=O, 11.10 poured into water to precipitate 0.95 g. of colorless solid, m.p. 81-108". The infrared spectrum of this material in cm. -l/78,1700 cm.-l/78, 1690 cm.-1/75, 1660 cm.-'/64; CC1, showed two unsaturated ketotic bands, yexoc 0 , r A r , 1600 cm.-l/49. 1673 cm.-'/50; "fenda c-0, 1662 an.-'/%. The ultraviolet Heating a 1.0-g. sample of the bromoketone I with 50 ml. spectrum for this mixed product was a n exact super-posiof dry spectrograde dioxane for 9 hours a t reflux temperature tion a t all points of a 67.5y0 endocyclic unsaturated ketorie gave n o appreciable change. Silver Nitrate in Ethanol.-A 0.69-g. (0.002 mole) sample 11, 32.5% exocyclic ketone 111 mixture: X 253, 29O(sh) of the bromo-ketone I and 0.35 g. (0.002 mole) of silver ni- 320(sh) mp (e 9,430, 6,810, 5,150) in 9570ethanol. Attempted Reactions with 2,4-Dinitrophenylhydrazine.trate weredissolved in 30 ml. of abs. ethanol and 2 ml. of Neither the bromo-ketone I nor the saturated ketone IV water. Silver bromide formation was observed within two (0;5 g., 0.00146 mole) reacted 011 standing for one week with minutes of mixing at room temperature. After standing at room temperature in the dark for 3.5 days, 0.336 g. (8970 0.08 g. (0.00292 mole) of 2,4-dinitrophenylhydrazinein solutions of 60 ml. of ethanol and 6 ml. of water containing yield) of silver bromide was removed by filtration. Concen4 ml. of concd. hydrochloric acid. The recovery of starting tration of the filtrate and purification of the residue by recrvstallization from methanol Droduced 0.46 P. (90% vield)' material mas 72y0in the case of the Iiromoketone I and 88?, for the snturated kFtonc I V o f t h e pure unsaturated ketoneII, m.p. 113-Tl4'0. LINCOLN, NEBR. Potassium Iodide in Dry Acetone.--d 0.97-g. (0.0058 mole) wmple of finely ground potnsTiurn iodide and 0.9 g . Lomow, EVGIAYD
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