A Study of Stereospecificity The Beckmann Rearrangement S. S. Siradling,' D. Hornick, J. Lee, a n d J. Riley St. Lawrence University, Canton, NY 13617
The Beckmann rearrangement has been investigated in some detail for almost a century ( I ) and is sometimes discussed in introductory organic texts (2).The reaction is usually presented as stereospecific (stereochemically different reactants produce stereochemically different products); however, isomerization of the oxime starting material and secondary cleavage reactions can complicate any analysis of the reaction. For use in our advanced laboratory program we have developed a Beckmann rearrangement which explores the concept of stereospecificity, and concurrently exposes the student to synthetic, spectrophotometric, and chromatographic processes. (II2 The reaction of benzvl methvl ketone (vhenvlacetone) .. . with hydroxylnmine yiilds t h c k and % oxime izuiners, I I and 111., in .inuronimatrl\. a 8:l rntii, ns dercrminrd frum thl: ititegration curve of the lH NMR spectrum of the oxime mixture's methvlene hvdroeens. (The ratio varies somewhat from one experiment to-another.) As indicated in the table, the E isomer(I1) shows a singlet for the methylene hydrogens a t about 6 3.4 ppm while the methylene hydrogens in the Z isomer(II1) are shifted further downfield to about 6 3.6 ppm because of the position of the hydroxyl group (3).The methyl hydrogens of both isomers absorb about 6 1.7 ppm and frequently overlap. ~
Chemical Shift V a l ~ e s ~ ~ ~ . ~ Com~ound
Ph
Proton Chemical Shins (ppm) CHD CHq OH NH
7.1
3.5
~~~
..
II
PhCH,CNHCH,(Vl
2.6(d)
-
7.5-8(b)
Conditions for performing the NMR analysesare given in the experimental. a Some other literature values for NMR spectral data of the reactants and products can be found in the articles cited in reference (7). O d = doublet. b = broad.
methvlene ~ r o t o n are s useful in a-alvzine the amide mixture.
A gaschromatographic analysis of t h i myde mixture confirms the isomer ratio, assumine identical resvonse factors for the two amides. We were unable to separate the oxime isomers by gas chromatography, however, though many different ads o r b e n t ~and conditions were attempted. Experimental 'H NMR spectra are obtained with a Perkin-Elmer R-24 (60 mHz) spectrophotometer using TMS as a standard. Spectra are run neat (ketone I and oximes I1 and 111)or in CCb (pure amides Wand Vand amide mixture of IV and V). Gas chromatographic separations are obtained with a Varian Aerograph Model 90-P instrument equipped with a thermal conductivity detector and using He as the carrier gas. A 5 ft, 20%DEGS column at 190" effects separation of the two amides with retention times of 13 and 15.8min with agasflow of 75 mllmin. Melting points are obtained using a Fisher-Johnsapparatus and are uncorrected. Aooraximate reaction times are eiven with each exoer.. " imental oraeedure. Care should he exercised in mine the acidic. ~.earrc ~ i v rwelit .+nhydride.nu ~ h a n ~bun,~ h~d~. pl~,,,ph, ~ l i ~ ruu. p n r IM&, ma1 thitjwl chltridr: i t is wg:c .led that pr. ~ v d u rtt~ ;tn;, thew reagents be conducted in a well-ventilated hood
Some difficultv was encountered in finding conditions under which the ;earrangement occurred without, presnmably, prior isomerization of the Z oxime to the E oxime (4). Use of phosphorous pentachloride or the procedure described by Craig and Naik (5) was not successful in effecting a stereospecific Beckmann rearrangement; however, the use of the phosphorous pentoxide-methanesulfonic acid reagent utilized bv Eaton and co-workers ( 6 ) works well. The oxime Benzyl Methyl Ketoximes (ll,ll~I( 4 h e misturr rearraiigej srrrt.oiperifi~-idlyt~ which is analy~cdwithuur puritirarim. T h e C:-c&nc ~ ~ r ~ * l u c e ~ Mix benzyl methyl ketone (phenylacetone) (I) (6.0 g, 0.045 moll, hydroxylamine hydrochloride (3.2 g, 0.046 mol), sodium acetate (3.1 N - b c n ~ y l , ~ v v t n ~ l ~ i dwhile e ~ l V the ) %-mimcgivri S-meth\.lg, 0.038 mol), 95%ethanol (20ml),water (15ml) and reflux for abnut Thc S \ l R t hmta.nl shirr valuc, and 2-~l1en\~IacetamiderVI. 45 min. Under reduced pressure (rotary evaporator) concentrate the mhtipficities for the two amides are given in the table. Both solution to a syrup, then add ethyl ether (25 ml). Transfer to a sepamides can be svnthesized in pure form for comparison purarator~funnel, wash the ether with saturated salt solution (threetimes poses. While oily the methyiene protons are useful for the with 25 ml each portion), and then dry the ether over anhydrous Na?SOa.Ether evaporation (steam bath in hood) gives a crude oxime ratio determination in the oxime mixture, both the methyl and mixture which is purified by reduced pressure distillation, b.p. 113-116' (3 mm). Occasionally a forerun of unreacted ketone is collected. Yields of purified oximes range from 35-70s. ' Aurhor lo whom corresponoence shoulo oe adoressed During me course of th s work, phenylacelone +%asclassil ed as The Beckmann Rearrangement (N-benzylacetamide, IV, and a contro ea substance am .IS commercial ava lao ry s, conseq-ently. N-methyl-2-phenylacetamide, V) ( 4 hr) limited. Procedures for preparing the compound are given in Org. Syn., Col Vol. II, pp. 389-392.The Drug Enforcement Administration may have some restrictions on the use of this material. ~~
~~~~~~
~~
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502
Journal of Chemical Education
g, 0.018 mol) are stirred with a magnetic stirrer at room temperature for about an hour and then heated to about 80" to complete solution. The oximes (2.0 g, 0.013 mol) are added slowly, and the mixture is heated and stirred a t 90-100' for about 30 min, then it is cooled and cautiously neutralized with 20%aqueous NaOH. The aqueous solution is transferred to a separatory funneland methylene chloride (30ml) is added to the solution after it has been used to rinse out the reaction flask. The aqueous solution is extracted a second time with methylene chloride (30 ml), the methylene chloride solutions are combined, washed once with saturated salt solution (25ml),dried over anhydrous NaBO4, decanted, and in a steam bath under a hood the methylene chloride is evaporated. The crude amides (50-90%yieids) ara analyzed directly by NMR and GC. N-Benzyiacetamide (IV)( I hr)
The amide is prepared by adding 1 ml benzylamine dropwise to acetic anhydride (4 ml) in an 8-in. test tube and warming on a steam bath for 20 min. Addition of ice water to the cooled tube causes precipitationofthe amide which is thenfiltered, washed withcold water, and dried. The crude material, m.p. 60°, is quite pure hut can be recrystallized. N-Methyl-2-phenylacetamide( V) (3hrj Reflux phenylacetic acid (5.0 g, 0.037 moll and thionylchloride (20
ml, 0.29 moll for 30 min and then distill (78') off excess thionyl chloride. In a400-ml beaker combine methylene chloride (60 ml), 40% aqueous NaOH (30 ml), and methylamine hydrochloride (5.0 g, 0.074 moll. In a hood add slowly, and with stirring, the red-brawn acid chloride to the amine biphase. A vigorous reaction ensues. Stir for 30 min, transfer to a separatory funnel, remove the lower organic layer and wash it with water, then with saturated saltsolution. and finallv dry over anhydrous NazS04.Evaporate the methylene chloride produce the crude amide which is recrystallized from ligroin, m.p. 57-58.5'. Literature Cited ! I . firerample cn:i'wry.F A and.hndbcw, K.1 ."AduancclOwnnicChm~..uy.~Pan 11. P'crun: Srh S.rk 19:'. 1.1) 3 2 6 3 ? : 1tu' ?'; ot \ l i r t ' '%%vanr 1 r l r v n , r ' - e w m .,.,I: d , ~ I . l ~ : > -ll#ll,Kem\ d 1 9 7 7 , ~1 ~ I : , $ n t , ~ . - r e n c e s , . w~.c:.nth..em8wr
