NOTES
AUQUST,1963 m.p. 235". Then 50 mg. (8.5%) of cyclic carbonate (XIV), m.p. 145-150°, and 120 mg. (12%) of unchanged XI were isolated, all three characterized by mixture melting points and comparative infrared spectra with authentic samples. The final residue (150 mg.) appeared to be mainly a mixture of the monobenzoate (VIII) and V, by ita infrared spectrum. The same results were obtained if a catalytic amount (6 mole %) of sodium hydride was employed. 3,4-Di-O-benzoyl-l,2 : 5,6-di-O-isopropylidene-n-mannitol (XIII).-Benzoylation of V or VI11 with excew benzoyl chloride in pyridine overnight a t room temperature gave an 85% yield of the dibenzoate as an oil which was free of hydroxyl absorption in the infrared. For analysis, the compound was absorbed from a benzene solution on a column of neutral alumina (Brockmann activity 111), then eluted with 1: 1 benzene-chloroform. The colorless oil had v:: 1715 (C=O); 1260,1100,1080 (C-0-C); 715 cm.-'(benzoyl CH); [a]"D f64.5 f 0.7" (0.60/0). Anal. Calcd. for CZeHsoOs: C, 66.4; H , 6.44. Found: C, 66.7; H , 6.24. Benzoate Equilibration of 3-O-Benzoyl-l,2 :5,6-di-O-isopropylidene-D-mannitol (VIII) with Sodium Hydride.-To a solution of 1.10 g. ( 3 mmoles) of dry V I I I in 60 ml. of reagent toluene wae added 130 mg. ( 3 mmoles) of 55% soduim hydride dispersion in mineral oil. After being refluxed for 90 min. protected from
2139
moisture, the mixture was spin evaporated to dryness i n vacuo. The residue was suspended in 20 ml. of water containing 0.2 ml. of acetic acid; the mixture was extracted with chloroform (four 20-ml. portions). Dried with magnesium sulfate, combined extracts were evaporated to dryness in vacuo. Crystallization from ethyl acetat&-petroleum ether gave 0.20 g. (25%) of debenzoylated product, V, identical with an authentic sample. The filtrate was evaporated to dryness in vacuo leaving 0.7 g. of a semisolid. Further traces of V were removed by absorption on neutral alumina (Brockmann activity 111) froin a hexane solution, then elution with 8 : 1 benzenemethanol. The resultant 0.55 g. showed two spots on silica thin-layer chromatography with benzenemethanol ( 7 : 1) as the solvent system and iodine vapor as the detecting agent. The two spots had Rr values of 0.77 and 0.56 and moved identically with authentic samples of VI11 and 3,4-di-O-benzoyl-1,2 :5,6-di-O-isopropylidene-~-mannitol (XIII), respectively.
Acknowledgment.-We wish to thank the Cancer Chemotherapy National Service Center, National Cancer Institute, and Starks Associates, Pnc., for largescale preparation of certain intermediates, mediated by contract no. SA-43-ph-4346.
Notes ultraviolet spectrum typical of a p-nitr~alkylbenzene.~ Furthermore, the infrared absorption pattern in the 5-6-p region was typical of p-disubstituted benzenes.6 The larger, faster-moving fraction could not be crystallized and showed a typical ultraviolet absorption specROGERKETCHAM, RICHARD CAVESTRI, AND D. JAMBOTKAR trum for an o-nitr~alkylbenzene.~In this case the infrared spectrum in the 5-6-11 region was typical of an Department of Pharmaceutical Chemistry, o-disubstituted beiizene.5 Oxidation of the solid nitraSchool of Pharmacy, University of California Medical Center, tion product with chromic acid gave p-nitrobenzoic San Francisco, California acid in 88% yield. The oil afforded 64% of o-nitrobenzoic acid under the same conditions. It is thus Received December 13, 1969 established that the cyclopropyl group, as expected, is an ortho-para director but that the major product is the In connection with another study12we had occasion ortho isomer. to refer to the ultraviolet spectrum of p-nitrophenylcyclopropane obtained by Levina, Shabarov, and Brown and Bonner have reported6 ortho-para ratios for nitration of toluene, ethylbenzene, cumene, and P a t a p ~ v . ~This spectrum, however, was inconsistent with data that we had accumulated2 and was not t-butylbenzene with concentrated nitric acid-concentypical of a p-nitroalkylbenzene. We, therefore, felt trated sulfuric acid a t 40'. In order that our result obliged to repeat their work in order to clarify the with phenylcyclopropane could be compared directly, problem. Nitration a t -40 to -20' with fuming we have repeated the nitrations of these four alkylnitric acid-acetic anhydride afforded a product whose benzenes with fuming nitric acid-acetic anhydride a t ultraviolet spectrum was nearly identical with that pre-40'. This reagent gives results which are very simiviously p ~ b l i s h e d . ~The proof of structure for the lar to those from the "mixed acid" except that the nitration product was based primarily on its oxidation yields are higher, the rate of decrease of the ortho-para with chromic acid to pnitrobenzoic acid in 70% yield.3 ratio is greater, and smaller amounts of smeta isomers When our nitration product was subjected to gas were observed. When the nitrating mixture was chromatographic analysis, two major components in a prepared a t room temperature and cooled to -40' ratio of 2: 1were observed. The smaller, slower-moving for nitration, the ortho-para ratio for the branched fraction crystallized on cooling (m.p. 32') and gave an alkylsubstituted benzene was much smaller, whereas with phenylcyclopropane the ratio was considerably (1) This work was supported, in part, by Cancer Research Funds of the University of California and b y an American Cancer Society Institutional higher. The nitration of phenylcyclopropane with this Nitration of Phenylcyclopropane. o r t h e p a r a Ratios for Nitration of Alkylbenzenes with Acetyl Nitrate'
grant 1N 33D. (2) L. A . Strait, R. Ketcham, and D. Jambotkar, paper presented a t 14th Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, March, 1963. (3) R . Ya. Levina, Yu. S. Shabarov, and V. K. Patapov, Zh. Obachch. K h i m . , 49,3233 (1959): J . Gen. Chem., U S S R , 39,3196 (1959).
(4) W. G . Brown and H. Reagan, J . A m . Chem. Soc., 69, 1032 (1947). (5) L. J. Bellamy, "The Infrared Spectra of Complex Molecules," 2nd Ed., John Wiley and Sons, Inc., New York, N. Y., 1958, pp. 67-61). (6) H. C. Brown and W. H. Bonner, J . A m . Chem. Soc., 7 6 , 605 (1954).
NOTES
2140 TABLE I Compound
HzSOeHNOs orthopara % yield
AoONO$ AoONO8 orthoorthopara % yield para
80" 1.78 94 1.76 Toluene 1.57" Ethylbenzene 0.93" 80" 0.86 93 0.90 Cumene .48" 80" .41 95 .27 t-But ylbenzene ,217" 80" .17 91 ,066 Phenylcyclopropane 2 . 1 0 70 1.99 93 4.0-4.7 a Ref. 6, the yields are given as approximately 80%. Nitrating reagent prepared a t -40". Nitrating reagent prepared a t room temperature.
latter reagent was not reproducible. The range of ortho-para ratios is given in Table I. The general agreement between the values obtained with acetyl nitrate and nitric acid-sulfuric acid mixtures indicates that the results are not due to the special ortho orientation property of acetyl nitrate which has been observed for nitration of anisole or acetanilide' with this reagent, but that phenylcyclopropane is inherently nitrat,ed preferentially in the ortho position. This contention was confirmed by the fact that nitration of phenylcyclopropane with nitric acid-sulfuric acid afforded a product mixture with an ortho-para ratio not greatly different from that obtained with acetyl nitrate. The results of the nitration experiments are in Table I. Bordwell and Garbisch recently have studied the reactions of acetyl nitrate with a series of styrenes and stilbenes.8 They have found that, although the major products of these reactions result from addition to the ethylenic double bond, there is, in most cases, some nuclear substitution. These workers did not determine the ortho-para ratios, but they did indicate that the amount of ortho-substituted product was in excess of the para isomer. The most common cases of high ortho-para ratios have been observed in nitrations of deactivated systems such as nitrobenzene, benzaldehyde, and ethyl benzoate.9 All of these compounds have unsaturated systems, and interactions between the substituents and the attacking nitronium ion have been postulated. In the case of styrene similar interactions can also be thought of as existing between the incoming nitronium ion and the vinyl group, thereby directing substitution preferentially to the ortho position. Stericly the cyclopropyl group should exert an effect similar to that, of the isopropyl group. However, the contraction in size introduced by the strained threemembered ring should make the cyclopropyl group somewhat smaller so that its steric effect should be intermediate between those of an ethyl and an isopropyl group. This should have led to an ortho-para ratio of about 0.75. The unsaturated nature of the cyclopropyl system has been observed in a number of situations.1° These manifestations of unsaturation have been related to the double bond character of the three-membered ring (7) For a discussion of the nature of this nitrating reagent see F. G. Bordwell and E. W. Garbisoh, Jr.. J . A m . Chem. Soc.. 89, 3588 (1960). (8) F. G. Bordwell and E . W. Garbisoh, Jr., J . Org. Chem., 9 7 , 2322 (1962). (9) G. S. Hammond, F. J . Modio, and R . M. Hedges, J . A m . Chem. SOC., 76, 1388 (1953): see, however, C. K. Ingold, "Structure and Mechanism in Organic Chemistry." Cornel1 University Press, Ithaoa, N . Y.. 1953, pp. 261-264.
VOL.28
caused by the highly strained carbon-carbon bonds which have approximately sp4 hybrid orbitals." The ortho-directing influence of the cyclopropyl system observed in this work appears to be still another example of the unsaturated character of this threemembered ring system. Phenylcyclopropane was prepared from styrene according to the methodI2 used by Doering and Hoffman to prepare norcarane from cyclohexene. The reaction between styrene and dibromomethylene, generated from bromoform by the action of potassium t-butoxide, afforded l-phenyl-2,2-dibromocyclopropane. Reduction with sodium and wet methanol afforded phenylcyclopropane. It should be pointed out that the earlier workers reduced their nitrophenylcyclopropane to the corresponding amine3 and that studies on this reduction product cannot be completely valid since it too must have been a mixture. Experimental13
l-Phenyl-2,2-dibromocyclopropane.-To a stirred solution of 0.33 mole of potassium t-butoxide (prepared by adding 13 g. of potassium to the t-butyl alcohol a t 70") and 181 g. (200 ml., 1.74 moles) of styrene in 400 ml. of t-butyl alcohol a t 15-20' was added dropwise 100 g. (0.4 mole) of bromoform. After stirring an additional 30 min., 300 ml. of water was added and the product extracted with pentane. The extract was dried over sodium sulfate and the solvent removed under reduced pressure. Vacuum distillation afforded 48.9 g. (5370) of l-phenyl-2,2-dibromocyclopropane, b.p. 90-100" a t 1 mm. Anal. Calcd. for CgHsBr2: C, 39.16; H, 2.97; Br, 57.92. Found: C,39.24; H, 2.96; Br, 57.66. Phenylcyclopropane.-To a stirred solution of 27.6 g. (0.1 mole) of l-phenyl-2,2-dibromocyclopropanein 100 ml. of ether was added dropwise a solution of 270 ml. of methanol and 50 ml. of water and portionwise 46 g. ( 2 moles) of sodium over a 3-hr. period. An additional 23 g. ( 1 mole) of sodium and 180 ml. of methanol and 20 ml. of water was added and the reaction mixture stirred an additional 2 hr. A final 23 g. ( 1 mole) of sodium and 100 ml. of methanol was added and the reaction mixture stirred for 7 hr . The reaction mixture was diluted with water and extracted with ether. The ether extract was washed with dilute hydrochloric acid and dried over sodium sulfate. Removal of the ether in vacuo and vacuum distillation of the crude product afforded 9.90 g. (84%) of phenylcyclopropane, b.p. 93-97" a t 45 mm . 0- and p-Nitrophenylcyc1opropane.-To a solution of 13.0 ml. of acetic anhydride and 4 ml. of fuming nitric acid a t -40" was added dropwise 3.25 g. (0.027 mole) of phenylcyclopropane a t a rate such that the temperature did not rise above -20". The reaction mixture was poured into hot water and the product was extracted with ether. The ether extract was dried and the ether removed under vacuum. Crude distillation gave about 5 ml. of product, b.p. 77-120" a t 1-3 mm. Gas chromatography (Aerograph Model A-90-C) on a 10-ft. silicone rubber, analytical column a t 135' showed two main bands in addition to smaller amounts of other substances.
(10) (a) R. A. Raphael in "Chemistry of Carbon Compounds," Vol. IIA,
E. H. Rodd, Ed., Elsevier Publishing Company, New York, N. Y., 1953, Chap. 1, pp. 25-28; (b) S. Sarel and E. Brewer, J . A m . Chem. SOC.,81, 6522 (1959); (0) E. N . Tractenberg and G. Odian, ibid., 80, 8018 (1958); (d) G. W. Cannon, A. A. Santilli, and P. Shenian, ibid., 81, 4264 (1959); (e) N . H. Cromwell, F. H. Sohumaoher, and J. L. Adelfang, ibid., 88, 974 (1961). (11) L. L. Ingraham in "Steric Effects in Organic Chemistry," M. 9. Newman, Ed., John Wiley and Sons, Inc., New York, N . Y.. 1956, Chap. 11, p. 518. (12) W. von E. Doering and A. K. Hoffman, J . A m . Cham. Soc., 7 6 , 6162 (1954). (13) Melting points and boiling points are uncorrected. Microanalyses are by the Microanalytical Laboratory, Department of Chemistry, Berkeley, Calif.
AUGUST,1963 Preparative scale gas chromatography on a 6-ft. Apiezon preparative column afforded sufficient quantities of the two main fractions for characterization. The largest of the two main fractions had the smallest retention volume. Its infrared spectrum showed a typical ortho-disubstitution pattern between 5 and 6 p and was, therefore, identified as o-nitrophenylcyclopropane. This substance is an oil (nZoD1.5606) 211, 249 mp; e which could not be made to crystallize; X:i:60" 1150; 4550. The smaller of the two main fractions, having the larger retention volume, showed an absorption pattern in the 5-6-p region typical of p-disubstituted benzenes and was identified as p-nitrophenylcyclopropane. This isomer is a low melting solid, m.p. 32-33'; X;:f6OH 218, 280 mfi ( e 8080, 11,000). Anal. Calcd. for CsHloNOz: C, 66.24; H , 5.56; N , 8.58. Found for o-nitrophenylcyclopropane: C, 65.98; H , 5.40; N, 8.54. Found for p-nitrophenylcyclopropane: C, 66.25; H , 5.54; N , 8.67. Oxidation of o-Nitrophenylcyc1opropane.-A sample of 0.50 g. (3.1 mmoles) of o-nitrophenylcyclopropane was heated under reflux for 2 hr. with a solution of 4.3 g. (43 mmoles) of chromic acid, 5.7 ml. of concentrated sulfuric acid, and 8.5 ml. of water. The reaction mixture was diluted with water and extracted with ether. The extract was dried and concentrated to give the crude product which on crystallization gave 0.33 g. (64%), m.p. 140-144' (lit.14 m.p. 147-147.5'), of o-nitrobenzoic acid, identical with an authentic sample (mixture melting point and infrared spectrum). Oxidation of p-Nitrophenylcyc1opropane.-A sample of 100 mg. (0.61 mmole) of p-nitrophenylcyclopropane was heated under reflux for 2 hr. with a solution of 0.85 g. (8.5 mmoles) of chromic acid and 1.1 ml. of concentrated sulfuric acid in 2 ml. of water. The reaction mixture was diluted with water and the solid was collected to afford90 mg. (88%) of p-nitrobenzoic acid, m.p. 24C242" (lit.14m.p. 239-240"), identical with an authentic sample (infrared spectra and mixture melting point). Nitrations of Alkylbenzenes and Analysis of the Product Mixtures.-To a solution of 26.1 g. (24 ml., 0.26 mole) of acetic anhydride and 10.9 g. (7.3 ml., 0.16 mole) of fuming nitric acid (density 1.49-1.50) a t -50' was added dropwise with stirring 0.05 mole of the alkylbeneene. The reaction mixture was allowed to come to room temperature (30 min.) and was poured into hot water. The product mixture was extracted with ether, the extract was dried, and concentrated to give the crude residue (always above 95% of the theoretical amount). This was dissolved in acetone in a 25-ml. volumetric flask and analyzed on a 10-ft. silicone rubber, analytical column (Aerograph A-90-C equipped with a disk integrator). The ratio of the areas under the two peaks was taken as the ortho-para ratio. Each analysis was carried out a t least three times; the analyses were reproducible within =klyo. The total yields based on the gas chromatograms were always above 90%. These values are subject to errors of j=3Y0, owing to variations in the sample size. The gas chromatograms gave evidence for only very small amounts of unchanged starting materials, meta isomers, and polynitro compounds. A second series of nitrations with acetic anhydridefuming nitric acid prepared a t room temperature was carried out in the same manner. Here also the yields were above 90%. In this case, nitration of phenylcyclopropane produced a rather wide range of ortho-para ratios. Nitration of Phenylcyclopropane with Nitric Acid-Sulfuric Acid.-A sample of 2.3 g. of phenylcyclopropane was nitrated in 3.83 g. sulfuric acid and 1.42 g. of nitric acid according to the method of Brown and Bonner.' The crude yield was 2.30 g. (78%). The chromatographic analysis is given in Table I. Infrared and Ultraviolet Spectra.-Infrared spectra were recorded on a Perkin-Elmer Model 21 spectrophotometer. Ultraviolet spectra were recorded in 95% ethanol on a Carey Model 11 ultraviolet spectrophotometer.
Acknowledgment.-The authors wish to thank Dr. L. A. Strait for many helpful discussions and Mr. Michael Hrenoff for determining some of the infrared and ultraviolet spectra. (14) M. Reimer and E. S. Gatewood, J . A m . Chem. So&, 42, 1475 (1920).
NOTES
2141
Competition Reactions of Cycloalkanes with Trichloromethanesulfonyl Chloride and Bromotrichloromethane EARLS. HUYSER, HAROLD SCHIMKE,~~ AND ROBERT L. BUR HAM'^ Department of Chemistry, University of Kansas, Lawrence, Kansas Received March 12, 1963
The suggestion was made in an earlier publication that the hydrogen abstracting radical in the peroxideand light-induced chlorinations of hydrocarbons with trichloromethanesulfonyl chloride (I) was not the trichloromethyl radicaL2 This conclusion was based on the difference in the relative reactivities of toluene and cyclohexane toward chlorination by I and toward bromination by bromotrichloromethane. Two different free radical chain sequences were suggested to account for the products obtained from the reaction of trichloromethanesulfonyl chloride with hydrocarbons (equation 1). ClaCSOzCl
+ RH +RCl + SO2 + HCC13
(1)
I CHAINSEQUENCE A
R.
+ ClsCSOzCl +RCl + C & c . + SO2 ClaC. + RH +HCCla + SO2
(2) (31
CHAINSEQUEKCE B
+ ClaCSOiCl +RCl + C13CSOz. ClsCSOz. + RH +ClaCSOzH + R . CIaCSOzH +HCCla + SO2
R.
(4) (5) (6)
In Chain Sequence A, the hydrogen abstraction from the hydrocarbon is performed by the trichloromethyl radical (equation 2) whereas in Chain Sequence B, the trichloro methanesulfinyl radical (ClaCS02.) is postulated to be the hydrogen abstracting radical (equation 5 ) . The trichloromethanesulfinic acid formed in this reaction is reported to be unstable, decomposing into chloroform and sulfur d i ~ x i d e . ~The peroxide- and light-induced brominations of hydrocarbons by bromotrichloromethane (equation 7) very likely involve the BrCCL
+ R H +RBr + HCC1,
(7)
free radical chain sequence (8 and 9), a sequence which almost certainly involves hydrogen abstraction
+ BrCCls +RBr + C1&. ClaC. + RH +HCCla + R . R.
(8) (9 1
by a trichloromethyl radical.& A comparison of the relative reactivities of the medium-size cycloalkanes toward halogenation by trichloromethanesulfonyl chloride (1) (a) Pacific Cniversity, Forest Grove, Ore., National Science Foundation Research Participant, Summer, 1961 (h) Grand View Collcge, Des Moines, Iowa, National Science Foundation Research Participant, Summer, 1962. (2) E. S. Huyser and B. Giddings, J . O r @ .Chem., 27, 3391 (1962,; E. S. Huyser, J . A m . Chem. Soc.. 8 2 , 5246 (1960). . 41, 38 (1927). (3) M. Battegay and W . Kern, Bull. S O Cchim., (4) E. S. Huyser, J . A m . Chem. Soc., 8 2 , 391 (1960);E. C. Kooyman and G. C. Vegter. Tetrahedron, 4, 382 (1958); see also G. A. Russell, C. DeBoer, and K. M. Deamond, J . A m . Chem. floc., 8 6 , 365 (1983). ~
2142
NOTES
and by bromotrichloromethane support the suggestion made previously that Chain Sequence B is operative in the chlorinations of hydrocarbons with trichloromethanesulfonyl chloride. The relative reactivities of cyclopentane, cyclohexane, cycloheptane, and cyclooctane toward reaction with trichloromethanesulfonyl chloride and bromotrichloromethane are shown in Table 1. These values were determined by competition reactions (see Experimental) of the cycloalkanes toward halogenation by the indicated reagent. That the same radical is not involved in the hydrogen abstraction in the two cases is evident from the different relative reactivities of these cycloalkanes toward halogenation by trichloromethanesulfonyl chloride and bromotrichloromethane. Cyclopentane and cyclohexane have essentially the same reactivity toward reaction with trichloromethanesulfonyl chloride, whereas cyclopentane is more reactive than cyclohexane in reaction with bromotrichloromethane. Although the relative reactivity of cycloheptane with respect to cyclohexane is very nearly the same toward both trichloromethanesulfonyl chloride and bromotrichloromethane, cyclooctane is a t least two times more reactive than cycloheptane toward the latter reagent, TABLE I RELATIVEREACTIVITIES OF CYCLOALKANES TOWARD REACTION WITH TRICHLOROMETHANESULFONYL CHLORIDE AND BROMOTRICHLOROMETHANE AT
80' No. of
Cycloalkane
Relative reactivity"
runs
ClaCSOzCl Cy clopentane Cyclohexane Cycloheptane Cy clooctane
l.OObf 0.07
14
1.00
..
2.67 f 0 . 1 6 4.2OCdz 0.04
4 3
BrCC13 Cyclopentane 1.57 f 0 . 1 7 18 Cyclohexane 1.00 .. Cycloheptane 3.30 f0.50 10 Cyclooctane 9.20df 0.54 7 Average a Relative to a unit reactivity of cyclohexane. deviation from average value obtained from number of runs indicated. Determined from relative reactivity of cyclooctane with respect to cycloheptane which was 1.57 f 0.02. Determined from relative reactivity of cyclooctane with respect to cycloheptane which was 2.79 f 0.18.
'
Two factors are probably responsible for the difference in the reactivities of the cycloalkanes toward hydrogen abstraction. These are (1) the relative stabilities of the cycloalkyl radicals that are produced, and (2) the relative stabilities of the cycloalkyl carbonium ions, a factor arising from polar contributions encountered in the transition state of the hydrogen abstraction reactions. Both of these factors may be im6+
VOL.28
involving other systems5 and, consequently, the predicted order of reactivity of the cycloalkanes toward hydrogen abstraction is cyclooctyl > cycloheptyl > cyclopentyl > cyclohexyl. The observed orders of reactivity of the cycloalkanes toward reaction with both trichloromethanesulfonyl chloride and bromotrichloromethane are consistent with this prediction. The lower degree of specificity found for the reactions with trichloromethanesulfonyl chloride suggests that the extent of bond breaking in the hydrogen abstraction step in the reactions of this reagent is less than that in hydrogen abstractions by the trichloromethyl radical. A lower degree of bond breaking compared to that encountered in the hydrogen abstractions by the trichloromethyl radical might well be expected if the Cl8CSO2. were the hydrogen abstractor (Chain Sequence B). The dissociation energy (Dc- H) for the carbon-hydrogen bond in the cycloalkanes is -94 kcal./mole.6 Hydrogen abstraction by a trichloromethyl radical is a process which is endothermic to the extent of -5 kca1.l mole (DC~G-H 90 kcal./mole6). The bond dissociation energy of an oxygen-hydrogen bond in (CH3),CO-H is -104 kcal./moleI7 and, although resonance stabilization of the trichloromethanesulfinyl radical might be expected to lower the oxygen-hydrogen bond dissociation :ij. :o: Clacs: f--, ClscS. :0: :0:
:0: Clacs:
:ij.
energy in trichloromethanesulfinic acid to some extent, it does not seem unlikely that D C l & - . R may be above 94 kcal./mole. This would make hydrogen abstraction from a cycloalkane by C13CS02.an exothermic reaction. Such a reaction, in terms of the Hammond postulateI8 might be expected to involve a transition state with less bond breaking than encountered in the endothermic hydrogen abstraction by Cl3C.. Contribution to the transition state involving stabilities of the cycloalkyl radical and carbonium ions would not be so great and, hence, the differences in reactivity less pronounced. Although apparently less selective as a halogenating agent that bromotrichlorometha.ne, trichloromethanesulfonyl chloride is a far more selective chlorinating agent than chlorine itself. The ratio of reactivities of CsH16:C7Hl4:C6H10:C6H12 toward chlorination with chlorine was found by Russella to be 1.5:1.0:1.0:1.0 a t 40'. In 12 M carbon disulfide, a solvent which markedly enhances the selectivity of chlorine atoms as hydrogen abstractors, the ratio of reactivities was found to be a 3.8:2.0:1.2:1.0 at 40' for C8H16:C7H14:C5~10:C6H1218 degree of selectivity somewhat less than we observed in reactions with trichloromethanesulfonyl chloride at 80'. Experimental
The nature of the products and the stoichiometry of the reactions of trichloromethanesulfonyl chloride and bromotrichloromethane with hydrocarbons are discussed in earlier reports (see ref. 2 and 3).
s-
[ R . . . H . . . , CCla]
(5) H. C. Brown, R. S. Fletcher, and R. B. Johannesen, J . Am. Chcm. G. Overberger. H. Biletch, A. B. Finestone, J. Lilker. and J . Herbert, ibid.. 7 6 , 2078 (1953). ( 6 ) Cf. C. Walling, "Free Radicals in Solution," John Wiley and Sons, Inc., New York, N. Y., 1957, Chap. 2, for tables of bond dissociation energies and discussion of their use in free radical reactions. (7) P. Gray and A. Williams, Chem. Reu., 69, 239 (1959). (8) G. S.'Hammond, J. Am. Chem. Soc., 77, 334 (1955). (9) G.A. Russell. ibid., 00, 4097 (1958). Soc., 7 8 , 212 (1951); C.
portant if there is a considerable amount of bond breaking in the transition state of the reaction as shown for hydrogen abstraction by the trichloromethyl radical. The inferred order of stability of the cycloalkyl radicals and carbonium ions based on kinetic measurements
NOTES
AUGUST,1963
2143
The relative reactivities shown in Table I were determined by competition reactions performed in the following manner. A mixture consisting of known amounts of two of the cycloalkanes was allowed to react with about a half of an equivalent amount of the halogenating agent. Benzene or chlorobenzene also was added in an amount equivalent to the cycloalkanes to serve as an internal standard for the gas chromatographic analysis. The reactions were performed in sealed tubes, induced with benzoyl peroxide, and allowed to proceed a t the indicated temperature until about 30-70% of the halogenating reagent had been consumed. Relative reactivity ratios, that is the ratio of the reaction rate constants of the particular cycloalkanes toward attack by the hydrogen abstracting radical, were calculated in the
hydrocarbon so that, on the average, the effective ionization potential for intermolecular attractions is that of a typical hydrocarbon. The electronic polarizabilities of water and hexane are 3.70 and 29.8 cm.a/mole.6 These values initially seem much different, but what governs interaction energies in solution is the polarizability per unit volume of the solvents. These values are 0.21 and 0.23 for water and hexane, respectively. The London dispersion forces will nearly cancel, and this result can be generalized to most systems of interest in organic chemistry. .k Table I presents data on the solubilities of a series of usual manner using the equation, = log ( A ~ n ~ t / A d / l o g kB R4XC104 salts. It is evident that the solubility in (B,n,t/Bfln), where the subscript, init and fin refer to the benzene (or ethanol) relative to water increases as the amounts of the cycloalkanes A and B before and after the resize of R increases. Such results cannot be rationalized action, respectively. The value for the amounts of the two cycloalkanes remaining after reaction were obtained by gas chromaby a consideration of ion-solvent electrostatic forces. tographic analysis of the reaction mixtures. Such forces must always be greater in water than benzene leading to the erroneous expectation that the salts will always be more soluble in water. n’either can such results be rationalized by a consideration of London Solubilities of Organic Salts in Hydrocarbons’ forcqs since the energies arising from such forces cancel, N. C . DENOAND HENRYE. BERKHEIMER as explained in the preceding paragraph. It is evident that any explanation based only on solute-solvent interPennsylvania State University, University Park, Pennsylvania action energies fails. Received January 31, 1963
TABLE I RELATIVE SOLUBIL~TIES OF R 4 N +SALTS(25’)”
It is known generally that salts of large organic ions are more soluble in organic solvents than salts of small inorganic ions. It might be imagined that this is a result of some specific attractive forces between organic molecules. However, solubilities of a wide variety of hydrocarbons in ~ a t e r have ~ , ~been correlated by an equation whose derivation specifically assumed that energies arising from van der Waals or London forces were the same for hydrocarbon-hydrocarbon interactions as for hydrocarbon-water attractive forces. This cancelling out of energies arising from London dispersion forces can be rationalized this way. Let us consider a molecule such as benzene immersed first in water and then in hexane. The energy arising from London forces between two small spherical molecules in the gas phase is given by this well known equation. E
=
+
(-3/’2)(ala~/re)Z1Zz/(Z1 ZZ)
(1)4
The polarizability, a,and ionization potential, I, for benzene are common factors for equation 1 applied to either benzene-water or benzene-hexane. The ionization potentials for water and hexane are 12.5 and 10.5 e . ~ .Although ~ the absolute difference between t’hese two numbers may seem large, the per cent difference is small when used in equation 1 so that only small energy differences arise from differences in ionization potential. The relative invariance of ionization potential is characteristic of compounds of C, H, 0, and N , aiid these are of primary interest in organic chemistry. When elements such as sulfur, iodine, etc., are introduced, their effect is overshadowed by the mass of (1) This research was supported in part b y a grant from the Petroleum Research Fund of the Amexican Chemical Society. Grateful acknowledgment is hereby made to the donors of this fund. (21 J. C. McGowan, J . A p p l . Chem., 1, 5120 (1951); 4, 323, 651 (1952); 4,
41 (1954). (3) N . Den0 and H . E. Berkheimer. J . Chem. Eng. Data, 4 , 1 (1960). (4) F. London, Trans. Faraday Soc., 88, 8 (1937). ( 5 ) F. H. Field and .J. L. Franklin, “Electron Impact Phenomena,” Academic Press. Inc.. New York, N. Y., 1957, pp. 116 and 122.
Salt KCIOdb RbCIOdb CSClOlb (CHa)rNCIOd (C,Hs)rNCIOd (CsHi)dNCIOa (CeHa)rNCIOd (CsHii)rNCIOd (CeHir)&ClOd (CHa)INIh (C~H&NI~ (CaHT)dNIb
-Solubility in moles/l.-Water Ethanol Benzene 0.149 ,071
,085 ,075 ,217 ,0204 ,000187 ,00067 ,00044
0 26 1.4
0.60
0.00065 00039 . on037 .00089 ,0114 ,0149 .00102 ,037 ,292 0.0045 ,353 .64
0.000165 .000113 .000075 ,000176 ,0011 1 ,871
-Relative solubilityEtOH-H20 CaH6-HzO 0,0044 ,0055 0344 ,0119 ,0525 .75 5.45 56 660
0.0022 00052 ,0037 .94 1.67 2000
0.017 .27 1.1
The solid phase in equilibrium with the saturated ethanol solution waa analyzed in each case and shown to be the simple C ~omitted O~ RINClO, salt (Table 11). Data on ( C ~ H Q ) ~ N is behause Ralph Seward of Pennsylvania State University found that the phase in equilibrium with the saturated solution in benzene contained benzene in the crystal lattice. The alkyl groups are the straight chain n-alky! groups except for CeHb, Data from A. Seidell, “Solubilities,” D. Van which is phenyl. Nostrand Co., Yew York, N. Y., 1960. 5
The answer lies in solvent-solvent forces and the principle of volume e n e r g i e ~ . ~ , ~Briefly, ,’,~ it costs energy to make a hole in the solvent to place a solute molecule or ion. This energy is the product, of the volume of the hole times the internal pressure of solvent. This energy will be greater for a solvent such as water with its high internal pressure arising from intermolecular hydrogen bonding. In contrast, this energy will be much smaller for most organic liquids in which the intermolecular forces are predominantly London forces. In the series listed in Table I, a3 the size of R increases, (6) Calculated by the familiar relation, (n* - l1(n* - 2 ) / ( M / e ) . (7) F. A . Longand W. F. McDevit, Chem. Reu., 61, 119 (1952). (8) H . Reiss, H. L. Frisch. E. Helfand. and J. L. Lebowitz, J .Chem. P h y e . , 84, 119 (1960); F. H . Stillinger, Jr., “Equilibrium Theory of Pure Fused Salts,” a chapter in “Selected Topics in the Physical Chemistry of Molten Salts.” Milton Blander, Ed., Interscience Publishers, Inc., New York, N. Y., 1962.
NOTES
2144
the volume energy increasingly favors greater solubility in benzene relative to water. At (C4Hg)rNC104, the volume energy effect equals the effect of the ion-solvent electrostatic energy and the salt is equally soluble in water and benzene. As the size of R increases beyond butyl, the ratio of solubility in benzene to solubility in water appears to increase without limit. The overshadowing of the electrostatic effect by the volume energy is, of course, aided by a decrease in the electrostatic effect with increasing size of R as well as the clustering of ions in the benzene phase.
VOL. 28 Kinetics of Reaction of Lithium Aluminum Hydride with Terminal Acetylenes in the Presence of Lithium Aluminum Amides’ SUNILKUMAR PODDER, TENG-MEI Hu, AND C. A. HOLLINGSWORTH~ Department of Chemistry, University of Pittsburgh, Pittsburgh 13, Pennsylvania Received January 14, 1963
It has been reported3 that lithium aluminum amides produced by the reaction of excess lithium aluminum hydride in ethyl ether with primary and secondary TABLE I1 amines and amine N-oxides are catalysts for the AND MELTING POINTSFOR TETRAALKYL reaction for lithium aluminum hydride with 1-hexyne ANALYSES NITROGEN AMMONIUM PERCHLORATES in ethyl ether. RAN+C10-Nitrogen, ?’&Found
R
Calcd.
a
8.07 Methyl Ethyl 6.10 4.90 Propyl Butyl 4.10 Pentyl 3.52 Hexyl 3.09 Prepared as described in from ethanol. 5
M.p., “C.
b
8.15 8.14 6.20 6.17 4.87 5.12 4.49 4.67 3.90 3.89 3.15 3.04 the Experimental.
*
237-239 207-209 110-116 105-106 Precipitated
Two practical results are suggested. If it is desired to conduct a reaction in a hydrocarbon solvent using a small inorganic ion, solubility can be achieved by using a salt of a large counter ion of the size of Czoor larger, preferably spherical to minimize micelle formation. Fortunately, such large salts generally have low lattice energies so that the absolute solubility will not be reduced to insignificance by high lattice energies. The second practical result is that large salts will be extracted from water by organic solvents and may be recrystallized from the organic solvent. These possibilities must be recognized in purification. Lest a misunderstanding arise, proteins, although large salts, will still be more soluble in water than benzene because each hydrogen bond between the protein and water changes the distribution coefficient by about 102.a Experimental The &N+C104- salts, ( R = methyl, ethyl, propyl, and phenyl) were prepared by treating a water solution of &N+Bror &N+I- (commercially available) with perchloric acid and washing with cold water with or without added alcohol to decrease solubility. For R = butyl, pentyl, and hexyl, the &N+I- salts were prepared by treating R8N with RI using procedures patterned after those of Smith and Frank.0 To prepare the perchlorate, a warm solution of silver perchlorate in ethanol was added to a warm solution of the R4N+I- salt in 9573 ethanol. The silver iodide was removed by filtration. Cold water was added to the filtrate and much of the ethanol allowed to evaporate. The precipitated R4N+C104- was filtered, washed with water, recrystallized from ethyl acetate, and waahed with ether in that order. The method used for R = methyl waa not applicable for R = CrCs because the &N+I- salts were too insoluble in water. The tetraphenylammonium perchlorate is a well known insoluble salt
(9) P. A . S. Smith and 9. Frank, J . Am. Chem. Soc., ‘74, 509 (1952). (10) H.Willard and L. Perkins, Anal. Chem., 26, 1634 (1953).
LiAlH,
+ 4HC=C-C4Hs
+LiA1(C=C-C4Hs),
+ 4H2 ( 1 )
With carefully purified 1-hexyne and the initial concentrations of 1-hexyne and lithium aluminum hydride 1 M and 0.25 M , respectively, and at 36’, the half-life of reaction 1 is about twelve hours when a catalyst‘is not present. The presence of a catalyst can so increase the rate that it has been described as “instantaneo~s.”~The reaction of phenylacetylene is similar to that of 1-hexyne except that the phenylacetylene reacts faster than hexyne in the absence of catalyst (half-life about one hour). The purpose of this note is to report the results of some kinetic studies of the catalyzed reaction with 1hexyne. Experiments were carried out to determine the dependence of the reaction rate upon the catalyst concentration, the 1-hexyne and lithium aluminum hydride concentrations, and the temperature. The kinetics was found to be complex, but susceptible to an approximate description that permits a comparison of the different catalysts. It was found that, except for the case of the lithium aluminum dicyclohexylamide, the kinetics might be described approximately as first order in 1-hexyne in the following sense : the logarithm of the hexyne concentration is a linear function of the time for a t least 70% of the reaction, even when the hexyne was in excess. Analogous plots of the logarithm of the lithium aluminum hydride concentration are not linear for cases in which the hydride was in excess. First-order rate constants were calculated from the slopes of the linear plots. The dependence of the rate constant on the catalyst concentration was found to be approximately linear, i.e. k
aM
+2 X
(sec.-’)
where (Y is a constant, and M is the molar concentration of the catalyst (in terms of amine added). Values of the constants a for all the catalysts studied are given in Table I. A value is given for dicyclohexylamine for comparison purposes, although the reaction in the presence of that catalyst is better described as second order (first order in hexyne and first order in hydride). However, even in this case, when the hydride was in excess plots of the logarithm of the hexyne aoncentration as a function of the time were sufficiently close to (1) This work was sponsored by the U. S. Army Research Offioe (Durham). (2) To whom inquiries should be sent. (3) G. B. Smith, D. H. McDaniel, E. Biehl. and C. A. Hollingsworth, J . Am. Chem. SOC., 84,3560 (1960).
NOTEB
AUGUST,1963 linearity to permit one to calculate approximate firstorder constants, from which a value of a was calculated. Activation energies were determined by obtaining rate constants a t three different temperatures between 15' and 40'. Since the reaction with no catalyst is very slow at 15' (and also follows no simple rate law, even approximately) it was necessary to use initial rates to determine the activation energy in that case. The activation energies decrease with increasing catalyst concentration and then level off to a constant value. These limiting constant values of E , are given in Table I for four different catalysts. It is probable that the lower effectiveness (smaller a) of the catalysts from diphenylamine and the dicyclohexylamine is not the result of higher activation energies, but rather of lower frequency factors. TABLE I CATALYTIC EFFECTSOF DIFFERENTCATALYSTS Source of catalyst
a (X
E . (kcal.)
Diethylamine 70 ( f10%) 13 ( f l ) Di-n-propylamine 60 .. Di-n-but ylamine 55 12 Diisobutylamine 6.5 .. Di-sec-bu t ylamine 4.0 .. Diphenylamine 1.0 10 Diisopropylamine 0.8 .. Dicy clohexylamine 0.6 12 No catalyst .. 17 0 These values are for 36.5' and the units are 1. X mole-' sec. -I The initial concentrations of lithium aluminum hydride and 1-hexyne ranged from 0.33 t o 0.41 M and from 1.00to 1.33 M, respectively. Experimental Materials.-1-Hexyne (Farchan) was found to contain traces of catalytic impurities after distillation. In order to remove these, most of the hexyne was treated with 2'370 hydrochloric acid solution, 2% sodium carbonate solution, wsshed with distilled water, dried wit!i anhydrous calcium chloride, passed through an aluminacolumn, and then distilled, b.p. 68" (745mm.). Further treatment had no observable effect. In one case the hexyne was passed over alumina and distilled without the pretreatment with acid, and the results were not noticeably different from those obtained with the hexyne which had been washed with acid. Phenylacetylene waa passed over alumina and distilled, b.p. 140' (730mm.). The liquid amines were freshly distilled; diphenylamine was Fisher Certified. Dilute ether solutions were made and then stored under refrigeration. The preparation of the lithium aluminum hydride solution has been described e1sewhere.s Apparatus.-The apparatus and method used to determine the reaction rates by following the hydrogen evolution previously has been described.' The reacting mixture was maintained under reflux and the temperature was varied by adding the appropriate amount of butane or hexane, or a mixture of these, to the ether solution. The total volume of hydrocarbon added never exceeded 21y0 of the total volume and no significant solvent effect other than the temperature effect was observed. Error Estimates.-The estimated error of f l kcal. for the activation energies is baaed on the maximum scatter that was observed. Most points were within f0.5 kcal. of the values given in Table I. It wm impossible to obtain a good estimate of the error in the values of a. The most rapid reactions were less reproducible than the slower ones. With some of the catalysts there was a definite decrease in the value of the rate constant with increasing initial lithium aluminum hydride concentration. This effect was not studied in detail and causes an increase in the uncertainty in the values of a. However, it is not likely that the error is great enough to cause the true relative order of the catalysts to be different from that shown in Table I.
2145
A Convenient Preparation of Allyllithium' JOHN J. EISCHA N D ALANM. JACOBS' Department of Chemistry, University of Michigan, Ann Arbor, Michigan Received February 13, 1963
The recently reported preparation of allyllithium by the metal-metal exchange reaction between allyltin derivatives and organolithium compounds3 has made accessible pure samples of this reactive organolithium compound. The chemical versatility of allyllithium has been exploited for the preparation of allyl derivatives of both metal and organic substrates in high yield^.^,^ However, the necessity of employing allyltin and organolithium starting materials detracts from the convenience of the method. On the other hand, alternate approaches to allyllithium, such as the interaction of allylsodium with lithium c h l ~ r i d e ,the ~ treatment of allyl Grignard reagents with metallic lithium,B and the cleavage of allyl halides by are less advantageous and often low-yielding processes. Wurtz coupling, leading to biallyl, is a prominent side reaction when allyl halides are exposed to lithium metal.3,7 As a sequel to the observation that anisole could be cleaved by lithium-biphenyl adducts in refluxing tetrahydrofuran (THF) solution, IC.* the analogous cleavage reaction of allyl phenyl ether was investigated. Indeed, the cleavage of the allyl ether by the 2:l lithium-biphenyl adduct proceeded rapidly even below 0'. Subsequently, it was found that lithium metal alone in tetrahydrofuran readily cleaved allyl phenyl ether a t - 15' to form allyllithium and lithium phenoxideg (equation 1). CH2=CH-CH2-O-CsHs
+ 2Li
-THF -15'
CH2=CH-CH2Li
+ CsH6--O-Li
(1)
The yields of allyllithium, as determined by the double titration method of Gilman and Haubein,lo ranged from 45%, in runs using stoichiometric quantities of lithium metal, up to 65%, when a sixfold excess of lithium was employed. Yet in instances where the yields of allyllithium also were determined by formation of chemical derivatives and subsequent isolation of the pure product (cf. infra), the resultant figures were ap(1) Paper IV in the aeries, Chemistry of Alkali Metal-Unsaturated Hydrocarbon Adducts. Previous papers are (a) J. J. Eisch and W. C. Kaska. J . O w . Chem.. 47, 3745 (1962); (b) J. J. Eisch and R . M . Thompson, i b i d . , 27, 4171 (1962); and (0) J . J. Eisch. ibid., 28, 707 (1963). (2) Undergraduate Research Participant. National Science Foundation, 1962. (3) D. Seyferth and M. A. Weiner, J . Org. Chem., 24, 1395 (1959); 26, 4797 (1961). (4) D. Seyferth and M. A. Weiner, Org. Syn.,41, 30 (1961). (5) E. J. Lanpher, J . A m . Chem. Sac., 79, 5578 (1957). (6) T. E. Londergon, U . S. Patent 2,734,091 (February 7 , 1956). (7) W. Kawai and S. Tsutsumi, J . Chem. Sac. Japan, Pure Chem. S e c t . 81, 109 (1900), report the preparation of allyllithium from allyl halides and lithium metal in ethyl ether solution. However, subsequent workers (ref. 3) were unable to achieve satisfactory results with this approach. (8) J. J. Eisch and W. C. Kaska. Chem. Ind. (London), 470 (1961). (9) Although the presence of biphenyl had little discernible effect upon the yields of allyllithium obtained from allyl phenyl ether and lithium metal, small amounts of biphenyl served as an excellent initiator for the cleavage. (Cf.Paper 111 of this series, J . Org. Chem., 28, 707 (1903), for the role of lithium-biphenyl adducts in such cleavage reactions). (10) H. Gilman and A. H. Haubein. J . A m . Chem. Sac.. 66, 1515 (1944).
NOTES
2146
proximately 5% higher. This suggests that the yields based upon the titration data are to be viewed as minimum values. The methods employed for the formation of chemical derivatives of allyllithium illustrate the high reactivity of this organometallic reagent in two types of reactions. The first involved the facile addition of allyllithium to the azomethine linkage of benzophenone anil" (equation 2), while the second was the substitutional allylation of chlorotriphenylsilanelz (equation 3).
CHz=CH-CHzLi
I
;:
gp)rSiC1
, (CBH~)&--CHZ-CH=CHZ(66%) (3)
If it is assumed that the precediilg reactions (equations 2 and 3) occur quantitatively, the yield of allyllithium (equation 1)must be a t least about 70%. The cleavage of allyl phenyl ether by lithium metal, therefore, constitutes a convenient method for the preparation of allyllithium from readily accessible and stable starting materials. Moreover, its preparation in tetrahydrofuran furnishes directly an excellent solvent medium for subsequent chemical reactions. l 3 It should be noted that the by-product, phenol, can be separated easily from the hydrolyzed reaction products simply by extraction of the lithium phenoxide with water. The striking ease with which allyl phenyl ether undergoes lithium metal cleavage contrasts sharply with the inertness of anisole toward lithium metal alone in refluxing tetrahydrofuran.l c 8 Rather it is with other allylic ether types, such as alkyl cumyl ethers14 and alkyl benzyl ethers,l5 that a similar facility toward metal cleavage must be sought. In a previous studylC the ease with which related unsaturated substrates were cleaved by lithium metal was correlated with the tendency of such substrates to form transitory lithium adducts. In this view the marked facility with which allyl phenyl ether is cleaved, compared with methyl phenyl ether, can be related to the resonance stabilization of both the incipient anionic fragments in the transition state of the cleavage reaction (equation 4). ~ O - C H 2 - - C H = C H 2 ZLi
VOL.28 Experimental16
Cleavage of Allyl Phenyl Ether.-To a 500-ml., three-necked, round-bottomed flask, equipped with a sealed paddle stirrer, a Friedrichs condenser surmounted by a nitrogen inlet tube and a pressureequalized addition funnel, were added 50 ml. of anhydrous tetrahydrofuran and 4.2 g. (0.60 g.-atom) of freshly cut lithium pieces (2 X 12 mm.). The system was cooled to -15 f 5" (external temperature) by an ice-salt bath while a solution of 6.7 g. (0.050 mole) of allyl phenyl ether17 in 26 ml. of anhydrous ethyl ether was added dropwise to the rapidly stirred lithium suspension. (If a pale green or biue color signaling the start of the cleavage was not noticed after a portion of the allyl phenyl ether was added, a pinch of biphenyl was introduced.lc) At the close of the 45-min. addition period the cooling bath was removed and the reaction mixture was stirred for an additional 15 min. The dark red solution was decanted through glass wool from the lithium metal and aliquots were analyzed by the usual double titration technique.10 Yields obtained in this manner ranged from 62 to 66%. The titrated yields of allyllithium ranged from 40 to 50q;b in runs in which 0.10 mole of the allyl phenyl ether in 25 ml. of ethyl ether were added to 0.22 g.-atom of lithium pieces in 50 ml. of tetrahydrofuran over a 60-min. period a t 0'. Derivatives of Allyllithium. (a) With Benzophenone Anil .-A solution of 12.85 g. (0.050 mole) of benzophenone anil in 50 ml. of dry benzene was added to the allyllithium solution obtained from the treatment of 0.050 mole of allyl phenyl ether with 0.60 g.-at,om of lithium, according to the first procedure described in the preceding section. The system was allowed to stir for 12 hr. and then was treated with water. The organic components were extracted with ether and the ether layer then dried with anhydrous calcium sulfate. The organic solvents were evaporated and the residue was taken up in a minimum of petroleum ether (b.p. 30-60'). This solution was chromatographed on an alumina column and the 1-allyl-1,l-diphenylmethyianilinewas eluted from the column selectively by additional portions of petroleum ether. The total yield of 1-allyl-1,l-diphenylmethylaniline thereby obtained was 10.2 g. (I%%), m.p. 75-77' (lit.I1 m.p. 78.580"). Recrystallization of this product from 957, ethanol raised the melting point to 77.579.5'. Admixture with an authentic sample caused no melting point depression. (b) With Chlorotriphenylsi1ane.-A solution of 13.28 g. (0.045 mole) of chlorotriphenylsilane in 50 ml. of anhydrous ethyl ether was added to a solution of allyllithium which was prepared in the aforementioned manner and was estimated to contain 0.031 mole by the double titration method.10 The resulting solution was stirred a t the reflux temperature for 12 hr. and thereupon hydrolyzed. The separated ether layer wm dried with anhydrous calcium sulfate and then evaporated. The residual colorless solid WEB recrystallized from 95% ethanol to yield 9.90 g. (66%) of allylt,riphenylsilane, m.p. 88-89" (lit.I2 m.p. 91"). (16) All organometallic reactions were conducted under a n atmosphere of dry, oxygen-free nitrogen. The tetrahydrofuran was purified b y BUCcessive treatments with sodium hydroxide pellets, sodium slices, and lithium aluminum hydride. The tetrahydrofuran was distilled from the lithium aluminum hydride directly into the reaction vessel. All glassware wau dried a t 120° for a t least 4 hr. All melting points are uncorrected. (17) L. Claisen. Ann., 418,78 (1919).
Cleavage of Silicon-Silicon Bonds on an Alumina Column
Amplification of these principles for the preparation of other useful organomet.allic compounds is being actively investigated. (11) Cf. H . Gilman and J . J. Eisch, J . A m . Chem. S o c . , 79, 2150 (1957), for the reaction of benzophenone anil with allyl a n d alkyl Grignard reagents. (12) R . H. Meen and H . Gilman, J. Org. Chem., 2 2 , 684 (1957). (13) For the enhanced rates of organolithium reaations in tetrahydrof u r a n , cf. H . Gilman a n d B. J. Gaj. ibid., 22, 447, 1165 (1957).and H.Gilman and S.Gray, ibid., 18, 1476 (1958). (14) K. Ziegler, F. Crossman, K. Kleiner, and 0. Schilfer, Ann., 473, 1 (1929); K. Ziegler a n d IT. Dislioh, Chem. Ber., 90, 1107 (19.57). (15) Cf. H. Gilman and G. L. Schwebke, J . Ore. Chem., 17, 4259 (l962), for the preparation of benzyllithium from such ether cleavages.
GHANSHAM R. CHAINANI, SHEILA COOPER, AND HENRY GILMAN Department of Chemistry, Iowa State IJniuersity, Ames, Iowa Received January 22, 1969
In a recent publication from these laboratories,' it was proposed that dilute hydrochloric acid promoted the hydrolytic cleavage of the silicon-silicon bonds in 1,4-dihydroxyoctaphenyltetrasilane (11) which were (1) A. W. P. Jarvie and H. Gilman, Cham. I n d . (London), 1271 (1960).
NOTES
AUGUST,1963 adjacent to the hydroxy groups. Isolation of symtetraphenyldisilane (IV) by chromatography on alumina of the crude hydrolysate obtained from 1,4dichlorooctaphenyltetrasilane (I) was taken as indication of the validity of this proposal. In this previous investigation, the 1,4-dihydroxy compound was not isolated in pure form; large amounts of its condensation product, octaphenyloxacyclopentasilane (111), were isolated. PhzPhzPhzPhz I I I, I C1-Si-Si-Si-Si-C1
I 1Hz0
PhQPhzPhnPhz
I.. I . I . I C1-Si-Si- Si-Si- OH
Y
\
PhzPhzPhzPhZ I I HO- Si- Si-hi-bi-0I-I
I1 PhzPhz I I HSi-Si-H
PhzSf0\SiPh2 I I PhzSi- SiPh2
++-
I11 -k 2 PhzSi(0H)z
IV Subsequent work in this area has shown that basic alumina is an effective reagent in causing scission of silicon-silicon bonds adjacent to hydroxy groups. Therefore, in the present work and probably in the previous investigation, it appears that siliconsilicon bond cleavage occurs during chromatography. When 1,4-dichlorooctaphenyltetrasilane was hydrolyzed in tetrahydrofuran by dilute hydrochloric acid, 1,4-dihydroxyoctaphenyltetrasilane (11) was the main product isolated. The high yield of this compound may be due to the rapid hydrolysis of both Si-C1 groups to Si-OH. Similarly, the product obtained from the reaction between Kipping’s Compound B2and phosphorus penta~hloride~ was hydrolyzed in a mixture of tetrahydrofuran and dilute hydrochloric acid to give the corresponding dihydroxy compound. When 1,4-dihydroxyoctaphenyltetrasilanewas chromatographed on an alumina column, there was obtained a 46% yield of sym-tetraphenyldisilane (IV) and a 4% yield of octaphenylcyclotetrasiloxane6 (PhzSi0)4which may have been formed by the action of base on diphenylsilanediol. 1,5-Dihydroxydecaphenylpentasilane afforded a 62% yield of 1,1,2,2,3,3-hexaphenyltrisilane (VI). This latter reaction supports the view that the dihydroxy derivative of Kipping’s compound B is 1,5dihydroxydecaphenylpentasilane and not (as previously designated) 1,6-dihydroxydodecaphenylhexasilane.4 Similarly, 1,5-dichlorodecaphenylpentasilane gave 1,1,-2,2,3,3-hexaphenyltrisilane (VI) in 50% yield Phz Phz Ph2 Phrr HS~-~i-di-F!i-OH V
Phi Phz Phz
+ Hdi-di-di-H
+ (HO)zSiPhz
VI
(2) F. S. Kipping and J. E. Sands, J . Chem. Soe., i i B 830 (1921). (3) D. R. Chapman, unpublished studiea. (4) A. W. P. Jarvie, H. J. S. Winkler, a n d H. Gilman, J . 070. Chcm., 97 614 (1962). (5) C. Eaborn, “Organosilicon Compounds,” Butterworths Scientific Publioationa, London, 1060, pp. 228-264. ( 6 ) G. L. Schwebke, unpublished studies.
2147
and 1,1,2,2,3,3,4,4-octaphenyltetrasilan-l-o1 (V)6 gave the same product in 51% yield. Instead of the previous silanol, its chloro derivative (l-chloro-1,1,2,2,3,3,4,4octaphenyltetrasilane) also could be used directly and gave a 52% yield of 1,1,2,2,3,3-hexaphenyltrisilane. 1,1,2,2,3,3-Hexaphenyltrisilan-l-ol was not isolated from the alumina column treatment of 1,4-dihydroxyoctaphenyltetrasilane. However, 1,1,2,2,3,3,4,4-octaphenyltetrasilan-1-01 (V) was obtained from 1,5-dihydroxydecaphenylpentasilane. In order to ascertain whether the silicon-silicon bond cleavage is enhanced by the presence of acids, 1,4-dihydroxyoctaphenyltetrasilane was treated with 6 N hydrochloric acid for two hours. No change in the infrared spectrum was observed and it seems that, under these conditions, no cleavage of silicon-silicon bonds or cyclization to octaphenyloxacyclopentasilane occurred. The alumina’ used in these experiments was basic and this basicity is considered to be responsible for the observed reaction. Whether the base effecting the cleavage is alumina itself or some other adsorbed inorganic base is not known. In any case, the diphenylsilanediol postulated as forming in the previous reaction scheme is probably bound chemically to the alumina through oxygen bonds. This would account for the absence of the product in the eluates. The course of the reaction might be as depicted. The same scheme might apply equally
Phz Ph? B-4-
+ HOdi-ki-
Phz
I
Phe
+B - O - S i q H
+ -$i-
4
BOH
Phz H4i-
well to the chloropolysilanes, with possible conversion of the silicon-chlorine linkage to silicon-oxygen. Silicon-silicon bond cleavage can conceivably occur a t other points in the reactants and product’s, which could account for the only moderate yields of silicon-hydrogen compounds. From these results, it may be expected that when polysilanes have strongly electron-withdrawing groups on the terminal silicon atoms they may be cleaved fairly specifically on alumina. Experimental Preparation of 1,4-Dihydroxyoctaphenyltetrasilane.-To 5 g. (0.0062 mole) of 1,4-dichlorooctaphenyltetrasilanein 100 ml. of tetrahydrofuran was added 150 ml. of dilute hydrochloric acid. The mixture wm stirred for 15 min. The hydrolyzate was then extractedwithether and0.35g. (7%)of solid, m.p. 183-185” (mixture melting point with starting material undepressed), was isolated as an insolub!e solid. The ether extracts, after drying over anhydrous sodium sulfate, were evaporated. All residues were fractionally crystallized from benzene-petroleum ether (b.p. 5060”) to give 2.65 g. (70%) of a solid, m.p. 208-210’. Recrystallization from benzene-petroleum ether raised the m.p. to 212213”. This solid, which showed no Si-H or Si-0-Si bands in the Infrared spectrum, but had a band due to Si-OH, is 1,4-dihydroxyoctaphenyltetrasilane . (7) The activated alumina for Chromatography wae obtained from t h e Chicago Apparatus Co., Chicego 22, Ill.
2148
NOTES
VOL.28
Anal. Calcd. for C48H1*02Si4:Si, 14.71. Found: Si, 14.50, The Structures of Substituted o-Quinone 14.51. Methide Trimers Similarly, hydrolysis of 1,5-dichlorodecaphenylpentasilane (19.2 g.) in tetrahydrofuran (150 ml.) using 80 ml. of 0.1 N hydrochloric acid gave 1,5-dihydroxydecaphenylpentasilane, ASHOTMERMAN, BENA. SHOULDERS, AND PETED. GARDNER 17.05 g. (92.2%); m.p. after recrystallization from cyclohexane and benzene, 172-174'; m.m.p. with an authentic specimen, Department of Chemistry, The University of Texas, 171-174'. Additional identification of the product was obtained Austin, Texas from the superimposability of the infrared spectra. 1,4-Dihydroxyoctaphenyltetrasilaneon an Alumina Column.Received February 16, 1963 1,4-Dihydroxyoctaphenyltetrasilane(1.45 g.) was placed on an alumina column. Elution with successive portions of petroleum ether (b.p. 50-60"), carbon tetrachloride, benzene, and ethyl The facility with which substituted o-quinone methacetate gave 0.32 g. (46%) of sym-tetraphenyldisilane, m.p. 76ides dimerize and trimerize was recognized as early as 78", and 0.02 g. (4%) of octaphenylcyclotetrasiloxane, m.p. 1907.' While a great deal of literature bearing on the 184-185', identified by mixture melting point and infrared specstructures of trimers has been written, most of it is tra. concerned specifically with the trimer of 3,s-dimethylTreatment of 1,4-Dihydroxyoctaphenyltetrasilanewith Hydrochloric Acid.-l,4-Dihydroxyoctaphenyltetrasilane (3.0 g.) in 10 quinone-(2)-methide (11) .z No less than three strucml. of ether was treated with 10 ml. of 6 N hydrochloric acid solutures have been proposed for this substance. The most tion for 2 hr. The ether layer was separated and evaporated to recent of these, the "benzodioxan" structure (111),was yield a solid, m.p. 19&200", which had an infrared spectrum suggesteda in 1941 and given additional support more identical with that of the starting material and contained no bands due to Si-H and Si-0-Si. recently. 1,5-Dihydroxydecaphenylpentasilaneon an Alumina Column .1,5-Dihydroxydecaphenylpentasilane(23.7 9.) was dissolved in benzene and placed on an alumina column 16 in. high and 2 in. in diameter. Fractions were eluted with benzene and, subsequent to recrystallization from acetone and methanol, gave 1,1,2,2,3,3hexaphenyltrisilane, 8.54 g. (62.1%), m.p. 9 5 9 7 " ; m.m.p. with an authentic specimen, 95-97'. In a second run, 1,5-dihydroxydecaphenylpentasilane (5.7 g.) was placed on an alumina column and eluted with benzene, to I give 0.4 g. of a solid, m.p. 97-98". This had the same infrared spectrum as the 1,1,2,2,3,3-hexaphenyltrisilaneisolated from I11 the chromatography of 1,1,2,2,3,3,4,4-octaphenyltetrasilane-101. There was no depression of the melting point of a mixture of Recent studies on the structure of the trimer of othe two products. Ethyl acetate elutions afforded 1.9 g. of a quinone methide itself led to the assignment shown in m.p. 180mixture of 1,1,2,2,3,3,4,4-octaphenyltetrasilan-l-ol, 181' (identified by mixture melting point and infrared spectrum); IV2and prompted a re-examination of the properties of and also some of the starting material (infrared). earlier reported substituted trimers. The trimer of 3,51,5-Dichlorodecaphenylpentasilane on an Alumina Column.dimethylquinone-(2)-methide and of 3-chloromethyl-51,5-Dichlorodecapheny1 pentasilane (29.5 g.) was dissolved in methylquinone-(2)-methide were studied as representabenzene and placed on an alumina column 18 in. high and 2 in. tive cases. Evidence is now presented establishing that in diameter. Elution of all the fractions with benzene and recrystallization from methanol and acetone gave 8.25 g. (50.0a/o) these two are related and have a ring system identical of 1,1,2,2,3,3-hexaphenyltrisilane,m.p. 9 5 9 7 " (mixture meltwith that of the parent (IV). They are, therefore, ing point with authentic specimen undepressed). The other formulated as V and VI, respectively. products were glues which could not be crystallized. The 1,1,2,2,3,3-hexaphenyltrisilanewas Identified additionally from the superimposability of its infrared spectrum with that of an authentic specimen. 1,1,2,2,3.3.4,4-0ctaphenyltetrasilan-l-ol on an Alumina Column.-A solution of 2.7 g. of 1,1,2,2,3,3,4,4-octaphenyltetrasilan-1-01 in 25 ml. of carbon tetrachloride was placed on an alumina column. Carbon tetrachloride and benzene elutions afforded0.99g. (5l%)of asolid,m.p.96-98', whichwas 1,1,2,2,3,3-hexaphenyltrisilane. Anal. Calcd. for C3BH3ZSi3: Si, 15.3. Found: Si, 15.40, 15.45. The infrared spectrum is similar to those of sym-tetraphenyl IV, R = R' = H disilane and 1,1,2,2,3,3,4,4-0ctaphenyltetrasilane, but possesses V, R R' = CHI an Si-H band of intermediate intensity. This trisilane was sepaVI, R = CHa, R' = CHzCl rated from the starting material, which was also partially eluted, Although V does not form carbonyl derivatives, the by its solubility in hot petroleum ether (b.p. 50-60"). I n the presence of an a,@-unsaturated ketone functionality preparatory method for the trisilane, better results were obtained with a long alumina column. was suggested by infrared data (vmax 5.91 p ) and conSimilarly, 50 g. of l-chloro-l,1,2,2,3,3,4,4-octaphenyltetra- firmed by quantitative microhydrogenation. It absilane afforded 18.5 g. (52%) of 1,1,2,2,3,3-hexaphenyltrisilane. sorbed 0.97 mole equivalent of hydrogen to afford a This latter reaction appeared to take a longer time than that dihydroketone (VII), m.p. 180-181°, vmaX 5.81 g. starting with the corresponding silanol. 4t6
P
Further reduction with lithium aluminum hydride
Acknowledgment.-This research was supported by the U. S. Air Force under contract AF 33(616)6463 and monitored by the Materials Laboratory, Directorate of Laboratories, Wright Air Development Center, Wright Patterson Air Force Base, Ohio.
(1) K.Fries and K. Kann, Ann., 863,339(1907). (2) S. B. Cavitt, H. Sarrafieadeh R., and P. D. Garduer, J . 070. Chem., 47,1211 (1962),and references cited therein. (3) G. Schiemann and K. Hultzsch, Naturwissenschaflen, 36, 124 (1948). (4) G. Schiemann, Reu. fac. sei. unia. Istanbul, l'IA, 290 (1952); Chem. Abstr., 48,3293(1954). (6) H. Civelekoglu, Rev. foe. rci. univ. I a t a n b d . , 18A, 14 (1953); Chem, Abstr., 48, 6139 (1954).
NOTES
AUGUST,1963 gave a carbinol (IX), m.p. 133-135'. Alternatively, reduction of V afforded an unsaturated carbinol (VIII), m.p. 145-146', which in turn gave I X upon hydrogenation. The presence of two benzenoid rings in this product is indicated by its ultraviolet absorption, Amax 280 and 287 mp; E 3890 and 3840, respectively.
HO,
,CHB
W C H , '
M
\
These assignments were corroborated by n.m.r. data. The lone olefinic proton of V was observed at 3.63 r and identified by comparison with the spectrum of IV. This proton is not strongly coupled indicating the absence of protons on adjacent carbon atoms. The small splitting (J = 1.3 c.P.s.) is due to coupling with the methyl group adjacent to the carbonyl (8.21 r ) . The methyl is observed as a doublet and the olefinic proton as a quartet. The methyl group at the bridgehead of rings C and D is at 8.37 while three of the aromatic methyls are at 7.83 r and the fourth a t 7.87 r . The higher field resonance of one aromatic methyl group is thought to be the result of steric repulsion by the bridgehead methyl group, an effect which has been observed with other substances in this laboratory. Additional examples must be examined, however, before it is possible to draw from these data the suggested stereochemical conclusions. The spectrum suggested the absence of protons on carbon atoms adjacent to ethereal oxygen. The relationship between V and VI was shown by hydrogenation of the latter; the product (VII) was identical with a sample obtained from V.
2149
The passage of 13.1 g. of 2-methoxymethyl-$,6-dimethylphenol through the 0.9-cm. tube a t 800-850" with nitrogen as a diluent gave crystalline material in the cold receiver as well as in the lower portion of the tube. This combined pyrolysate was recrystallized from ethyl acetate-petroleum ether to give 6.4 g. (60%) of colorless solid, m.p. 199-201'. This material was shown to be identical with that obtained from 2-chloromethq-l4,6-dimethylphenol' by means of the usual comparisons. This substance exhibits ultraviolet absorption a t 206, 221, and 281 mp with extinction coefficients 63,000, 21,700, and 2910, respectively. Carbonyl absorption in the infrared is at 5.91 p . Anal. Calcd. for C27H3008: C, 80.56; H, 7.51. Found: C, 80.66; H , 7.60. Hydrogenation of 3,5-Dimethylquinone-(2)-methide Trimer (V).-A solution of 0.109 g. of the trimer in 15 ml. of ethanol was stirred with 0.075 g. of 10% palladium-carbon (pre-saturated) under 1 atm. of hydrogen. Hydrogen uptake ceased at 5.8 ml. (9770 for one double bond). The product, isolated in the usual manner, melted at 179-180" without purification. Several recrystallizations from ethyl acetate-petroleum ether gave a pure sample, m.p. 180.0-180.5". This dihydro trimer (VII) exhibits carbonyl absorption in the infrared at 5.81 p . Ultraviolet maxima a t 280 and 287 mp have e values 3890 and 3840, respectively. This substance, like its precursor, does not form carbonyl derivatives. Anal. Calcd. for Cz7H3203: C, 80.16; H, 7.97. Found: C, 79.84; H, 7.79. Lithium Aluminum Hydride Reduction of 3,s-Dimethylquinone-(Z)-methide Trimer (V).-A mixture of 1.O g. of trimer V, 0.095 g. of lithium aluminum hydride and 20 ml. of purified tetrahydrofuran was stirred at room temperature for 24 hr. Excess reductant was destroyed by the cautious addition of water and then dilute hydrochloric acid. The mixture was extracted with ether and the extract washed thoroughly with water. Drying (sodium sulfate) and evaporation of solvent followed by recrystallization of the residue from ethyl acetutepetroleum ether gave 0.70 g. (70%) of colorless carbinol ( I I I I ) , m.p. 145-146". This substance exhibits no carbonyl ahsorption in the infrared. I t absorbs in the ultraviolet at 280 nip ( e 3620). Anal. Calcd. for C27H3203: C, 80.16; H , 7.97. Found: C, 80.00; H, 7.71. Tetrahydro-J,S-dimethyIquinone-(2)-methide Trimer (1x1.( A ) From VI1.-A solution of 0.30 g. of dihydro trimer (1.11) and 0.10 g. of lithium aluminum hydride in 20 ml. of tetrahydrofuran was stirred at 30' for 12 hr. Moist ether was slowly added followed by dilute hydrochloric acid. The usual isolation by ether extraction and processing of the extract gave a viscous gum. Chromatography (alumina) of a benzene solution of t,he product afforded crystalline material. Two recrystallizations from petroleum ether gave 0.080 g. (27%) of IX, m.p. 133.5135.0". The infrared spectrum of this substance exhibits no absorption in the carbonyl region. Anal. Calcd. for C27H,,O,: C, 79.76; H , 8.43. Found: C, 79.33; H, 8.27. (B) From VII1.-A solution of 0.35 P. of trimer carbinol IVIII) in 4Oml. of ethanol was shaken with 6.20 g. of 10% palladiumcarbon under 1 atm. of hydrogen. When hydrogen was no longer absorbed, the catalyst was removed by filtration and the product isolated by evaporation of solvent. Three recrystallizations from petroleum ether afforded 0.115 g. (33%) of I X , n1.p. and m.m.p. 133.5-134.0". The infrared spectrum is identical with that of material prepared from T'II. Reduction of 3-Chloromethyl-S-methylquinone-(2)-methide Trimer (VI),-The chloro trimer (VI, 6.0 g.)' in 100 ml. of ethyl acetate was shaken with 5.05 g. of triethylamine and 1.0 g. of 10% palladium-carbon under 3 atm. of hydrogen. When hydrogen uptake ceased, the mixture was processed as described before to give a solid product. Recrystallization from ethanoipetroleum ether afforded 3.0 g. (647,) of VII, m.p. 177-liS". A mixture melting point determination and a comparison of spectra established the identity of this product. \
Experimental
2-Methoxymethyl-4,6-dimethylphenol (I).-The methiodide of 2-dimethylaminomethyl-4,6-dimethylphenoP (32.5 g.) was heated under reflux in 200 ml. of 10% methanolic potassium hydroxide for 3 hr. The cooled solution was diluted with a large volume of water and extracted with two portions of ether. The aqueous layer was cooled and acidified whereupon an oily layer separated. It was isolated by several extractions with ether. The combined extracts were wsshed with saturated aqueous sodium bicarbonate and with water and were then dried with anhydrous sodium sulfate. Freeing of solvent a t an aspirator and distillation of the residue through a short column gave 7.35 g. (44%) of 2-methoxymethyl-4,6-dimethylphenol( I ) , b.p. 46" (0.1 mm.). Anal. Calcd. for C I ~ H U O ~C,: 72.26: H , 8.49. Found: C, 72.34; H, 8.57. 3.5-Dimethvlauinone-(2 )-methide Trimer (V).-The Dvrolvsis system employe2 was that described for the preparation of t h e parent trimer ( IV).2 Conditions used were those described. (6) P. D. Gardner, H. 8. Rafsanjani, a n d L. Rand, J . Am. Chem. A"., 81, 3364 (1959).
~~~
Acknowledgment.-The authors are indebted to The Robert A. Welch Foundation for the financial support of this study. (7) K.Hulccsch, J . prokt. Chem., l W , 180 (1941).
NOTES
21 50
VOL.28
A New Method for Preparing
Experimental'
S-Aryl-2,3-dihydro-1H-1,4-benzodiazepines
7-Chloro-5-phenyl-2,3-dihydro-l H-1 ,Cbenzodiazepine.-7Chloro-l,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 7 9.)
THEODORE S. SULKOWSKI AND SCOTTJ. CHILDRESS Research and Development Division, Wyeth Laboratories, Inc., Radnor, Pennsylvania Received March 1, 1963
A recent publication' has described the preparation of 7-nitro-5-phenyl-2,3-dihydro-l H-l,4-benzodiazepine from 2-chloro-5-nitrobenzophenone and ethylenediamine. We have had occasion to prepare benzodiazepines of this type, but have found this method to be of limited use. Nitro activation of the aryl chloride appears to be necessary since treatment of 2-bromo-5chlorobenzophenone with ethylenediamine afforded no benzodiazepine. A more versatile method is the lithium aluminum hydride reduction of 5-aryl-l,3-dihydro-2H1,4-benzodiazepin-2-0nes. NH
NH
I
CsH5 NH
LiAIHd
Cl
C=N I
,C Hz \
NH qH::iH~ C1 \
COCH3
I
N,
NH
waa added in portions to a stirred suspension of lithium aluminum hydride (1.6 g.) in anhydrous ether (200 ml.). The mixture waa heated under reflux for an hour and the excess hydride was decomposed by careful addition of water. The ether layer waa separated, dried over magnesium sulfate, and evaporated to dryness. Recrystallization of the residue from ethanol afforded 3.5 g. of product, m.p. 174-176'. Anal. Calcd. for C16H13ClNZ: C, 70.17; H , 5.11; C1, 13.81; N, 10.91. Found: C, 70.32; H , 5.07; GI, 13.6; N, 10.98. 7-Chloro-5-phenyl-3,3-tetramethylene-2 ,3-dihydro-IH-l,4benzodiazepine, m.p. 180-181 (from ethanol), was similarly prepared in 42y0 yield. Anal. Calcd. for C1QH&lNg: C, 73.46; H, 6.16; GI, 11.41; N, 9.01. Found: C, 73.16; H , 5.92; C1, 11.20; N, 8.71. 7-Chloro-4-hydroxy-5-phenyl-2,3,4,~-tetrahydro-l H-l,4-benzodiazepine.-7-Chloro-l,3dihydro-5-phenyl-2H - 1,4 - benzodiazepin-2-one 4-oxide (10 g.) was treated with lithium aluminum hydride (2.8 9.) in anhydrous ether (250 ml.) as in the preceding example. There was obtained 7 g. of product, m.p. 170-172'. Anal. Calcd. for C16H16ClN20: C, 65.57; H , 5.50; C1, 12.90; N, 10.20. Found: C, 65.87; H, 5.26; C1, 13.0; N , 10.32. 7-Chloro-5-phenyl-2,3dihydro-lH-l,4-benzodiazepine 4Oxide.-A suspension of the previous solid (12 g.), mercuric oxide (20 g.), acetone (250 ml.), and water (25 ml.) waa stirred for 3 hr. a t room temperature. The mixture was filtered and the filtrate was evaporated to dryness in vacuo. Recrystallization of the residue from 95% ethanol afforded 8 g. of product, m.p. 247248 '. Anal. Calcd. for C16H&1N20: C, 66.05; H , 4.81; C1, 13.00; N, 10.27. Found: C, 66.20; H , 4.92; C1, 13.3; N , 9.92. 7-Chloro-5-o-chlorophenyl-2,3-dihydro-1H-l,4-benzodiazepine 4-Oxide, m.p. 215-217' (from ethanol), was prepared similarly (45%) from 7-chloro-5-o-chlorophenyl-1,3-dihydro-2H-l,4-beneodiazepin-2-one 4-oxide,6 but without the isolation of the intermediate 7-chloro-5-o-chlorophenyl-4-hydroxy-~,3,4,5-tetrahydrolH-l,4-benzodiazepine. Anal. Calcd. for C16H&l2N*O: C, 58.65; H , 3.94; C1, 23.09; N, 9.12. Found: C, 58.94; H, 4.04; C1, 23.50; N , 8.87. l-Acetyl-7-chloro-5-phenyl-2,3-dihydro-l H-l,4-benzodiazepine 4-Oxide.-A solution of 7-chloro-5-phenyl-2,3-dihydro-lH-l,4benzodiazepine 4-oxide (4 9 . ) in acetic anhydride (20 ml.) was warmed on a steam bath for 0.5 hr. The solution was evaporated to dryness in vacuo. The residue was recrystallized from ethanol to afford 1.5 g. of product, m.p. 222-224". The carbonyl absorption band was a t 6.02 f i . Anal. Calcd. for C1~H16ClN202: C, 64.87; H, 4.80; GI, 11.27; N , 8.90. Found: C, 64.90; H , 4.76; Cl, 11.2; N, 9.13. O
Reduction of 7-chloro-&phenyl- 1,3-dihydr0-2H- 1,4benzodiazepin-Pone with lithium aluminum hydride in ether has afforded 7-chloro-5-phenyl-2,3-dihydro-lH1,4-benzodiazepine in good yield. 7-Chloro-5-phenyl3,3-tetramethylene-2,3-dihydro-lH-l,4-benzodiazepine (4) Melting points are uncorrected. (5) This compound, m.p. 249-250' deo., was prepared by C. Gochman was prepared similarly. following method A of ref. 3. Lithium aluminum hydride reduction of 7-chloro-5phenyl-l,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide gave 7 - chloro - 4 - hydroxy - 5 - phenyl - 2,3,4,5 - tetraThe Decomposition of Methylethylphenylbenzylhydro-lH-l,4-benzodiazepinewhich could be oxidized by mercuric oxide to afford 7-chloro-5-phenyl-2,3-diphosphonium Acetate hydro-lH-1,4-benzodiazepine4-oxide. The 5-o-chlorophenyl analog was made by the same route. KENNETH L. MARSIAND G. DAVIDHOMER' Since a large variety of l13-dihydro-2H-1,4-benzodiazepin-2-ones with differing substituents in positions Long Beach State College, Long Beach 4, California 3,5,6,7,8, and 9 has been disclosed,"a this method can Received February 21, 1963 afford a varied group of 2,3-dihydro-lH-1,4-benzodiazepines. A few examples of thermal decomposition of phosThe 5-aryl-2,3-dihydro-lH-1,4-benzodiazepines were phonium carboxylate salts have been studied.2 These potent central nervous system depressants in animal tests. ( I ) Petroleum Research Fund Scholar, 1901-1962. (1) J. A. Hill, A. W. Johnson, and T. J. King, J . Cham. h e . , 4430 (1961). (2) L. H.Sternbach and E. Reeder, J . Org. Chem., 46,4936 (1961).
(3) 9. C. Bell, T. S. Sulkowski, C. Gochman, and 8. J. Childreas, ibid., 47,562 (1902).
(2) (a) E. A. Letts and N. Collie, Phil. Mag., 49, 183 (1886); (b) N. Collie, J . Chem. SOC.,18, 636 (1888); (0) D.B. Denney and L. C. Smith, Chem. Ind. (London), 290 (1961); (d) D. B. Denney and L. C. Smith, J . Org. Chem., 97, 3404 (1962).
NOTES
AUGUST,1963 include the acetate, benzoate, and oxalate salts of the tetzaethylphosphonium ion, 2a tetramethylphosphonium
+
benzoate, 2b and the phosphobetaines, (C6H5)3P(CH,) nCOz- where n = 1,2,3.2c It was the purpose of this research to investigate the thermal decomposition of the unsymmetrical phosphonium salt, methylethylphenylbenzylphosphonium acetate. This compound was chosen because of the possible information it might provide concerning the comparative ease of elimination of the groups bonded to the phosphorus atom in a nucleophilic attack by the acetate ion.3 More importantly, the systern seemed well suited for subsequent stereochemical studies of the type conducted by McEwen, VanderWerf, and coworkers4 who have investigated other nucleophilic reactions involving the enantiomersb of this phosphonium ion. The outcome of the reaction differed substantially from that of decomposition reactions reported for the symmetrical phosphonium i o n s . 2 a , b , d The analytical data are summarized in Table I. TABLE I ANALYSIS OF REACTION PRODUCTS Method of analyais
Product
Toluene Acetic acid Methyl acetate Ethyl acetate Phenylacetone Methylethylphenylphosphine oxide cis-2-Methyl-l,3-diphenyl1-propene trans-2-Methyl-l,3-diphenyl1-propene Ethylphenylbenz ylphosphine (as the oxide)
Yield,"
%
22 40 16 Trace 5 69
V.p.cb Titration V.P.C. V.P.C. V.P.C. Infrared V.P.C.
12
V.P.C.
16
Product isolation
16
a 100 x moles product/molea reactant. matography.
Vapor phase chro-
A mechanistic accounting for the reaction products is somewhat speculative a t this point; however, it seems reasonable that the acetate ion may be involved in a nucleophilic attack on a pentacovalent intermediate. 0
+ II CHa
(CHa)(CzHs)(CsHs)(CsHsCHz)i: 6-
OAc-
(CHa)(CzHs)(CsH6)(CsHsCHz)P-~CHa + (CHa)(CzHs)(CsHs)P=O
+ (CHsC0)zO + Ce.HsCHz:-
This proposal has some support in work of other^*^,^ where it has been noted that ethers are produced from the decomposition of certain phosphonium alkoxides a t lower temperatures.
--OR'-
R ~ ~ R !
R*P=O
+ R ~ ' O+ R : -
(3) G. W . Fenton and C. K. Ingold, J . Chom. Soc.. 2342 (1828).
(4) (a) K . F. Kumli, W. E. McEwen, and C. A. VanderWerf, J . A m . Chem. Soc.. 8 1 , 3805 (19.59); fb) C. B. Parisek. W . E. McEwen, and C. A. VanderWerf. ibid., 84, 5503 (19603; A. BladbFont, C. A. VanderWerf. and W. E. McEwen, ibid., 82,2396 (1960); W. E. McEwen. A. Blade-Font. and C. A. VanderWen, ibid., 84, 677 (1962). ( 5 ) K. F . Kumli. W. E. McEwen, and C. A. VanderWerf, ibid., 81, 248 (1959). (6) M. Grayson and P. T. Keough, ibid., 84, 3818 (1860).
2151
It is likely that phenylacetone is formed by reaction of the benzyl anion with acetic anhydride, and that the isomeric olefins are produced either by a Wittig reaction of the ylid of the methylethylphenylbenzylphosphonium ion with phenylacetone, or by an alternate or competing reaction involving addition of the benzyl anion to phenylacetone with subsequent dehydration of the tertiary alcohol thus formed. That the yields of the olefins from the pyrolysis reaction are nearly equal does not rule out the Wittig pathway to the olefins, since at the elevated temperature of the pyrolysis low stereospecificity would be expected. The appearance of methyl acetate and ethylphenylbenzylphosphine among the reaction products is probably the result of a nucleophilic displacement by acetate ion on the phosphonium ion, and has its analogy in the work of Denney.2c.d Stereochemical assignments for the olefins were made on the basis of the positions of the higher wave-length bands in the near ultraviolet which are usually shifted to higher frequencies for olefins with sterically interacting cis substituents7 (benzyl-phenyl interaction in this case), and comparison of these o l e h s with those isolated from the isomer mixture obtained from sulfuric acid dehydration of methyldibenzylcarbin~l~ in which trans-2-methyl-l,3-diphenyl-l-propene (phenyl and benzyl groups trans to each other) should predominates9 Experimental 10
Methylethylphenylbenzylphosphonium Iodide (I).-This compound was prepared by the method of Raileyll and melted a t 162-1 64'. MethylethylphenylbenzylphosphoniumAcetate Hydrate (11).To a solution of 24.5 g. (0.066 mole) of I in 350 dry methanol was added with stirring a t room temperature 12.12 g. (0.0726 mole) of dry, powdered silver acetate. The reaction mixture waB protected from atmospheric moisture and heated a t 40' with stirring for 6.5 hr. The brown precipitate (16.22 9.) was removed by filtration in a drybox and the methanol distilled under reduced pressure. The viscous liquid was placed in a vacuum desiccator over phosphorus pentoxide and after 5 days it crystallized into a mass of light gray crystals. Two recrystallizations from anhydrous ethyl acetate yielded extremely hygroscopic, fluffy white crystals which were dried in vacuo over phosphorus pentoxide a t 56" for several days. This treatment produced a substance of m.p. 104.2-105.3' (with softening). Anal.l2 Calcd. for Ci8HzaOzP~z/aHzO: C, 68.77; H , 7.80; P , 9.86. Found: C, 68.52; H , 7.83; P , 10.23. Pyrolysis of 11.-I1 (14.36 g., 0.0457 mole) waa placed in a 25-ml. round-bottomed flask attached to a 44-cm. vacuum jacketed Vigreux column equipped for vacuum distillation. Air was swept out of the system with dry nitrogen. The flask and contents were immersed in an oil bath a t 85" and the temperature of the oil bath raised steadily 280" over a period of 22 min. where it waa maintained for an hour. First evidence of reaction occurred a t a bath temperature of 200" and the reaction became vigorous a t 230". The first fraction ( I ) , 2.93 g., was collected to approximately 120" a t atmospheric pressure. The pot was then cooled to 80", the system placed under vacuum, heating resumed, and a second fraction ( 2 ) consisting of 7.95 g. was collected to 165" (9 mm.). A third fraction ( 3 ) of 1.68 g. was ob(7) A. E. Gillam and E. S. Stern, "An Introduction to Electronic Absorp tion Spectroscopy in Organic Chemistry," 2nd Ed., Edward Arnold Ltd., London, 1957, pp. 267-275. ( 8 ) R . M. Caves, R. L. McLaughlin, and R. H. Wke, J . A m . Chem. Soc., 76, 522 (1954). (9) H. C. Brown and M. Nakagawa, zbid., 77, 3614 (1955). (10) All melting points and boiling points are uncorrected. (11) W. J. Bailey, S. A. Burkler, and F . Markbcheffel, J . Ore. Chem., 46, 1986 (1960). (12) Microanalyses were performed by Schwarzkopf Microanalyt~eal Laboratory, Woodside 77, N. Y.
NOTES
2152
tained at 172-230' (9 mm.) and solidified to a yellow solid on cooling. Analysis of Fraction 1 .-Vapor phase chromatographic separation and examination of infrared spectra indicated the presence of acetic acid, toluene, methyl acetate, and ethyl acetate (trace). Toluene and methyl acetate were determined quantitatively on a IO-ft. Ucon column, and acetic acid by titration with standard base. The fraction contained 31% toluene, 19% methyl acetate, and 38% acetic acid by weight. Water waa not determined in this fraction but would theoretically amount to 13.675. Analysis of Fraction 2.-A small portion of fraction 2 waa extracted with water, the water evaporated, and the infrared spectrum of the residue in chloroform shown to be identical in every respect with that of the authentic material prepared from methylethylphenylbenzylphosphoniumiodide by treatment with sodium hydroxide.48 The methylethylphenylphosphine oxide waa analyzed spectrophotometrically in chloroform solution with a Baird Atomic double beam infrared spectrophotometer using the absorption peak a t 8.95 mfi and waa shown to represent 67% by weight of fraction 2. Another portion of fraction 2 when treated with 2,4-dinitrophenylhydrazine reagent13 yielded the 2,4-dinitrophenylhydrazoneof phenylacetone, m.p. 152-154'; reported" m.p. 152.5-153.5", m.m.p. 152-154". Vapor phase chromatographic analysis of fraction 2 on a IO-ft. Ucon column gave the following results: 4% phenylacetone, 19% trans-2methyl-l,3-diphenyl-l-propene,and 14% cis-2-methyl-l,3-diphenyl-1-propene by weight. The latter two compounds displayed retention times and ultraviolet spectra identical with the authentic materials prepared by dehydration of methyldibenzylcarbinol.* The isomera were separated on a 10-ft. Ucon column from the fraction boiling a t 162-164' (9 ".).Is The cis and trans isomers absorbed a t 218, 245 and 218, and 249 mfi, respectively. Fraction 3 .-Fraction 3 waa recrystallized twice from ethyl acetateligroin to yield a compound of m.p. 112-113"; reported16 m.p. for ethylphenylbenzylphosphineoxide, 110-11lo. This compound melted undepressed with purified ethylphenylbenzylphosphine oxide prepared by air oxidation of ethylphenylbenzylphosphine.le
Acknowledgment.-This research was supported by a type B grant from the Petroleum Research Fund. Appreciation also is expressed to Mary E. Pate, Richard McAtee, and Larry Becker for their help in the initial phase of this work. (13) R . L. Shriner. R. C. Fuson, and D. Y. Curtln, "The Systematic Identification of Organic Compounds," 4th Ed., John Wiley and Sons,Inc., New York, N. Y . , 1960, p. 111. (14) R. T. Gilsdorf and F. F. Nord, J. Am. Cham. Soc., 74, 1837 (1952). (15) Although the mixture of isomers has been reported (ref. 8) this is apparently the first account of their separation. This fraction was shown to consist of 61% trans and 39% cis isomer. (16) J. Meisenheimer, J. Casper, M. Horing, W. Lauter, L. Lichtenstadt, and W. Samuel, Ann., 449, 213 (1926).
Mechanism Study of a Benzilic Acid-Type Rearrangement KENNETH S. WARREN,0. K. NEVILLE,* AND EDWARD c. HENDLEY3 Oak Ridge National Laboratory, Union Carbide Nuclear Company, Oak Ridge, Tennessee Received January 18, 1963 a,a-Dibromopropiophenone (I) rearranges to atrolactic acid (I11 or IV) during treatment with concentrated sodium hydroxide solution. It has been sug(1) This paper is based upon work performed a t Oak Ridge National Laboratory, which Is operated for the Atomic Energy Commission by Union Carbide Corp. (2) Nuclear-Chicago Corp., 345 East Howard Ave., Des Plaines, Ill. (3) Department of Chemistry, Mississippi State University, State College, Miss.
VOL.
CsHsC*OCBr2CHa I
Route A
+
l-
C~HSC*O-COCH~ I1
k / L
C6H6 *-COCHa
I
AH
CsH&(OH)CHs A*OOH I11
28
CeHsC*O-
I
:-CH3
Route B
CsHsC*(OH)CHs
AOOH IV
gested4 that the reaction proceeds by way of the intermediate, methyl phenyl diketone (11), which then undergoes a benzilic acid rearrangement. When these authors subjected dibromo compound I to dilute alkali, no atrolactic acid was recovered; the sole product was 2,5-diphenyl-1,4-benzoquinone, formed in 13% yield by an aldol condensation of two molecules of the diketone. The action of concentrated sodium hydroxide on I1 produced atrolactic acid in low yield, whereas dilute alkali produced only tar. The use of carbon-14 as a tracer has been applied here in following the mechanism in the rearrangements starting with both the dibromo compound and the diketone. These two compounds (I and 11) were prepared, labeled in the a-position. The atrolactic acid produced by rearrangement of these compounds was degraded by oxidation to acetophenone and carbon dioxide. In both cases essentially all of the original carbon-14 was found in the carbon dioxide. Since this labeled carbon atom was originally adjacent to the phenyl group, 100% phenyl migration must have occurred in both alkaline-catalyzed rearrangements, thereby eliminating route B as a possible mechanism. It is possible that the carbonyl group of 11, a to the phenyl group, may be the preferred one for hydroxyl ion attack. However, if hydroxyl ion attack were rapid and reversible, the observed preference of route A also could be explained as due to a tendency of the phenyl group to migrate in preference to the methyl group. If methyl phenyl diketone is the intermediate in the rearrangement of a,a-dibromopropiophenone, it is obvious that the rearrangement of the diketone must be much faster than the rate of formation. Any appreciable concentration of the diketone would lead to the aldol condensation mentioned previously. Experimental
(a,a-Dibromopropio-l-C1~)-phenone (I).-To 9.7 g. (0.4 mole) of magnesium turnings contained in a 250-ml., round-bottomed, three-necked flask was added slowly a solution of 53.6 g. (0.5 mole) of ethyl bromide in 95 ml. of ether. While the flask waa cooled in ice, 12.1 g. (0.1 mole) of carbonyl-labeled benzamide waa slowly added under dry nitrogen. After a reflux period of 24 hr. the reaction mixture waa hydrolyzed with ice and sulfuric acid and extracted with ether. From the extract waa obtained 7.5 g. (56% yield) of propiophenone. One gram of the unpurified propiophenone waa treated with a solution of 2.50 g. of bromine in 7.5 ml. of chloroform and allowed to stand a t 25.5" for 0.5 hr. before it waa refluxed for 4 hr. The solvent waa carefully removed to give 2.13 g. (97% theoretical yield) of crude a ,a-dibromopropiophenone (I). Hydrolysis and Rearrangement of a,a-Dibromopropiophenone. -The crude dibromide (I)wae stirred vlgorously with 42.6 g. of 20% aqueous sodium hydroxide for 3.5 hr. The aqueous phase waa extracted with ether and acidified with concentrated hydro(4) R. Levine and J. R. Stephens, J. Am. Cham. Soc., 79, 1642 (1050)
NOTES
AUGUST,1963 chloric acid. The precipitated crystalline atrolactic acid wm removed by filtration and sublimed a t 70 to 75"; m.p. 91 to 92". Methyl Phenyl Diketone-3-C14(II).-This compound was prepared by the treatment of carbonyl-labeled propiophenone with butyl nitrite, followed by acid hydrolysis of the resultant monoxime. Rearrangement of Methyl Phenyl Diketone.-The diketone (11), dissolved in a large volume of ether, was stirred vigorously for 1 hr. with an equal volume of 20% sodium hydroxide solution maintained a t 0". Under these conditions, a yield of about 25% of the desired atrolactic acid (111)could be isolated after neutralization of the aqueous layer. Oxidation of Atrolactic Acid (III).-In a typical degradation, 83 mg. of I11 wae decarboxylated a t room temperature by treating with a mixture of 44 mg. of chromium trioxide and 2 ml. of glacial acetic acid in a small flask connected to a barium hydroxide absorption train. The apparatus was swept with nitrogen gas and the evolved carbon dioxide was converted to barium carbonate. The precipitated barium carbonate was washed with water and centrifuged several times before air drying. The residue in the reaction flask was extracted with ether and the ether extract was washed with sodium bicarbonate and then evaporated. The residual acetophenone was converted to the semicarbazone which after two crystallizations from 25% alcohol melted a t 198'. Radioactivity Assay of Oxidation koducts.-The determination of carbon-I4 was conducted by the wet combustion of small samples of the barium carbonate and acetophenone semicarbaside according to the technique of Raaen and R ~ p p .The ~ results are given in Table I.
2153
The product from the action of three moles of sulfuryl chloride and subsequent hydrolysis on Knorr's pyrrole, 2,4-dicarbethoxy-3,5-dimethylpyrrole(I), is a mixture of the 5-formyl- and 5-carboxypyrroles. E'ischer, et aL,l reported the isolation in high yield of a hexachloro derivative (11) from the action of six moles of sulfuryl chloride on I. Structure I11 was assigned to I1 apparently on the basis of the analyses for C, N, C1, and OCzHs. However, hydrolysis with potassium hydroxide did not yield the tetracarboxypyrrole diester, but rather fragmented the compound. The hexachloro derivative .could be reduced to 2,4-dicarbethoxy-3methyl-5-hydroxymethylpyrrole and oxidized to a compound containing one additional oxygen and one less chlorine.
111
TABLE I RADIOACTIVITY OF CARBON l 4 IN
I.(C./MMOLE
-Rearrangement Dibromo compound I
experiment withDiketone I1
Original material 1.028 0.935 Acetophenone semicarbazide 0.00579 0.005 Barium carbonate ,909" .857" a The approximately 90% material balances of the radiocarbon are attributed to exchange with dissolved carbon dioxide in the wash water (Melvin Calvin and co-authors, "Isotopic Carbon," John Wiley and Sons, Inc., New York, N. Y . , 1949, p . 124) as well as exchange with atmospheric carbon dioxide ( M . D. Kamen, "Isotopic Traces In Biology," 3rd Ed., Academic Press, New York, N. Y . , 1957, p. 308) during drying of the wet, centrifuged barium carbona,te. ( 5 ) V. F. Raaen and G . A . Ropp. Anal. Chem., 26, 174 (1953).
The Structure of Hexachlorinated 2,4-Dicarbethoxy-3,5-dimethylpyrrole JAMESH. MATHEWSON Department of Chemistry, University of California, Berkeley, California Received December 10, 1962
The n.m.r. spectrum of I1 shows three bands: a triplet a t 6 1.37 (p.p.m., tetramethylsilane, 0), a singlet at 2.24, and two almost coincident quartets centered at 2.62 and 2.64. The ratios of triplet/singlet/quartet areas are 6 : 3 :4. This shows that I1 retains a methyl group (the singlet) which was corroborated by a Cmethyl determination. The infrared spectrum of I1 shows no absorption in the pyrrole XH stretching region (3400-3500 cm.-l) or the pyrrole ring vibration region (1470-1600 ~ m . - l ) . ~Two bands are observed in the carbonyl region at 1740 and 1760 em.-', above the normal pyrrole ester position^.^ There is a band at 1612 em.-', the position reported for the imine stretching band of A1-pyrrolines.6 The ultraviolet spectrum of I1 shows only end absorption with a slight shoulder a t 215 mp ( E 4850). This supports a structure for IT in which the imine is not in conjugation with the a ester carbonyl. For example, glyoxylic acid semicarbazone absorbs a t 252-253 mp ( e 12,400), whereas acetone semicarbazone absorbs at 224 mp ( e 11,000).6 The iodide test for N-C1 was negative.' The evidence points clearly to structure IV for the hexachloro derivative 11. Experimental
Chlorination with sulfuryl chloride followed by hydrolysis has been a commonly used technique for the oxidation of a-methyl substituents on In general, one, two, and three moles of sulfuryl chloride yield, respectively, the mono-, di-, and trichloromethylpyrroles which can be hydrolyzed to the hydroxymethyl-, formyl-, and carboxypyrroles. I n this reaction, p methyl groups are not attacked and unsubstituted positions are chlorinated.
2,4-Dicarbethoxy-3-methyl-5-trichloromethyl-2,3,4-trichloroA1(s)-pyrroline (I1 and IV).-Knorr's pyrrole (I) in ether wa8 chlorinated with freshly distilled sulfuryl chloride as described by Fischer, Sturm, and Freidrichl; m. p. 72" (lit.'m.p. 72"). Anal. Calcd. for C12H13CleNOa: C, 32.12; H, 2.9; C1, 47.5; C-CHs, 3/446; mol. wt., 446. Found: C, 32.2; H, 3.0; C1, 47.0; C-CHa, 3.1/446; mol. wt., 426 (osmometer). A sample of I1 in ether acidified with acetic acid was shaken with aqueous potassium iodide. An iodine color developed only after 4 days. The n.m.r. spectrum was taken in carbon tetrachloride with tetramethylsilane as internal standard with a Varian Model A-60
( 1 ) H . Fischer, E. Sturm, and H. Friedrich, Ann., 461, 244 (1928). (2) H . Fischer and H. Orth. "Die Chemie des Pyrrols," Vol. I, Akad. Verlaa., Leipaig, 1934, p. 76. (3) A . H. Corwin, W . A. Bailey. and P. Viohl, J . Am. Chem. Soc., 64, 1267 (1942); A . H. Corwin and J. L. Straughn, zbid., 70, 1418 (1948).
(4) U. Eisner and R . L. Erskine, J . Chem. Soc., 971 (1958). ( 5 ) J. H. Burckhalter and J. H. Short, J . Oru. Chem., 23, 1278 (1958). (6) J. A. Olson, Arch. Biochem. Biophvs., 86, 225 (1959). (7) M. Z. Barakat and M. F. Abd El-Wahab. Anal. Chem.. 16, 1973 (1954).
VOL. 28
NOTES
2 154
spectrometer. The infrared spectrum was taken in potassium bromide with a Perkin-Elmer Model 221 spectrophotometer. The ultraviolet spectrum was taken in ethanol with a Cary Model 14 spectrophotometer.
Acknowledgment.--The author wishes to thank Professor H. Rapoport for advice and encouragement. This investigation was carried out during the tenure of a fellowship from the U. S. Public Health Service.
Configuration Assignments in Symmetrical Alkyl- Aryl Pinacols' WILLIAMA. MOSHERA N D NED D. HEINDEL* Department of Chemistry, University of Delaware, Newark, Delaware Received March 8, 1963
In a study of the mechanism of the pinacol-pinacolone rearrangement it became necessary to synthesize and characterize pure diastereoisomeric forms of PhRC(OH)C(OH)RPh where R = methyl, ethyl, and npropyl. These diols previously have been reported as dimeric reduction products of their respective ketonesacetophenoneJ3propiophenone, 4andn-butyrophenone6or by appropriate Grignard additions to benzil.8,6 In only one case has a configurational assignment of the dl and meso isomers been established and that by a synthesis of optically active and inactive 2,3-diphenyl2,3-butanediol from ( - )-methylbenzoin.' Chiurdoglu and others have reported that hydrogen bonding studies could distinguish threo and erythro isomers in a series of aliphat,ic 1,2-diols and we have found such studies can provide information upon which to base reliable configurational assignments in aryalkyl diols. By examination of the hydrogen bonding patterns of the three isomeric pairs (see Table I), it is possible to divide the diols into two sets. One member of each pair (11, IV, and VI) shows only a free hydroxyl peak in the 3605--3611-cm.-1 region with an attendant shoulder while the other member shows a sharp, distinct pair of free and bonded peaks (in addition to the concentration dependent intermolecular bands). Steric considerations dictate that in order to exhibit intramolecular hydrogen bonding between hydroxyls the meso isomers would have to exist in an unfavored conformatmionin which the bulky phenyl groups on adjacent carbons would be in close p r ~ x i m i t y . ~The dl-diastereoisomers can intramolecularly bond their (1) Presented a t the Fourth Delaware Valley Regional Meeting, American Chemical Society. J a n u a r y , 1962. (2) A portion of this work is taken from the M.S.thesia of Ned D . Heindel, National Science Foundation Predoctoral fellow, 1959-63. (3) Rainsrt-1,ucaa and M. Salmon-Legagneur, Bull. 8oc. chim. France, (4) 46, 718 (1929).
(4) G . Ciamician and P. Silber, Atti Accad. Nazi. Lincei, Mem. Ciasee Sci. F i s . Mat. .Vat. S e z . , (5) 33-1. 860 (1014). (5) I. Nazarov. .4nn. Leningrad State C. Chem. Ser., 1, 123 (1935); Chem. A h s f r . , 31, 6617 (1937). (6) E. Chu and J. Chu. J . Chznese Chem. Soc.. 10, 11 (1943). (7) 17. Cram and K. Kopecky, J . Am. Chem. Soc., 81, 2748 (1959). (8) G . Chiurdoglu, R. de Groote, W. Masschelein, and M. H. van Risaeghem. Bull. s o r . chim. Belges. 7 0 , 342 (1961): Chem. Abstr.. 68, 8185 (1962). (9) E. Eliel, "Stereorheinistry of Carbon Compounds," McGraw-Hill Hook Co.. l n c . . N P WYork, N. Y . , 1962, pp. 132-133.
TABLE I HYDROQEN BONDINQ IN PhRC(0H)RPh R
Methyl I I1 Ethyl 111 IV n-Propyl
Free -OH M.p., OC. (em.-')
Bonded -OH (cm.-1)
AS-
Av
Position of C-0 (om.-])
signment
122-123" 117-118"
3615 3580 ( 8 ) 3605 3570 (ah)"
35 1143 1191 dl 35 1126 1167 meso
113b 138-13gb
3616 3572 (a) 3609 3570 (w)'
46 1143 1182 dl 39 1125 1164 meso
V 95-96c 3615 3569(s) 46 1144 1180 dl VI 128-12gd 3611 3561 (m)E 50 1124 11.59 meso a Prepared as in ref. 3. Prepared as in ref. 4. Prepared as in ref. 5 . Prepared as in ref. 6. e The characterization of the position of the bonded peak is approxims,te since it appears as a shoulder or broad weak band.
hydroxyls when the phenyls are in a favored trans orientation. Hence I, 111, and V might be assigned the dl-configuration, and 11, IV, and VI the meso. The same conclusion might be reached by considering that in dl isomers the intramolecularly bonding hydroxyls can attain a perfect cis orientation without the severe phenyl-phenyl eclipsing that would be necessary in the meso form. This conclusion is strengthened by examination of the bands associated with C-OH stretching modes for the tertiary hydroxyl which appear a t 1140 to 1190 cm.-'. Each of the diols 11, IV, and VI shows double absorption peaks in this region which shift to higher frequencies in those diols which show strong intramolecular hydrogen bonding, I, 111, and V.lo The shift is exactly in the direction predicted for increased rigidity imparted to the C-0 bond by intramolecular associations. I t is also possible that the C-0 bond shifts in going from rneso to dl isomers are due to differences in dipoledipole interactions in the two configurational species. Support for this possibility arises from the fact that the peak displacements show a remarkable, constancy, between 16 and 20 cm:-', in the various isomers (see Table I). If the C-0 bond shifts were solely due to increased rigidity imparted t,o the bond by increased intramolecular association in the dl forms t8henone might expect a proportional increase in the C-0 shift differences (between dl and meso forms of the same compound) as the hydrogen bond becomes tighter. Such a correlation is not, observed. The constancy of the C-0 peak displacements suggests that they might possibly serve as qualitative and quantitative tools for identifying such compounds in mixtures. I t also has been observed that the small amount of intramolecular hydrogen bonding which occurs in the meso forms increases as one proceeds from methyl to ethyl to n-propyl. This is explained by the conformational consideration that the unfavored rotomer for intramolecular bonding in meso becomes less and less (10) Similar shifts of this kind have been previously reported and correlated with hydrogen bonding, H. E . Zimmerman and J . English, Jr., J . Am. Chem. S o c . , 7 5 , 2368 (1953). (11) L. J . Rellamy, "The Infrared Spectra of Complex Molecules." John Wiley and Sons, Inc., New York, N. Y., 1958, pp. lOE110. (12) Cram and &pecky, ref. 7, have observed but not explained these differences in the 8 . 8 - p region for the diastereoisomeric acetophenone pinacols and have employed them for quantitative analysis purposen.
NOTES
AUGUST,1963 unfavored as the increasing bulk of the R groups approaches that of the phenyl. The increase in the strength of the hydrogen bond, as reflected in A u , I 3 from 35 in the meso-methyl to 50 cm.-I in meso-n-propyl is expected in light of previous observations that replacement by increasingly bulky alkyl groups on the carbons bearing the hydroxyl and phenyl reduces the 0-C-C angle and brings the hydroxyls into closer proximity. This is in accord with the Thorpe-Ingold deformation hypothesis that says when steric repulsions increase one of the angles a t a carbon atom, the opposite angle is d e c r e a ~ e d . ~ ~ . ’ ~ While these observations support the conclusion that in this series simple intramolecular bonding between hydroxyls is occurring, it is impossible to eliminate completely the possibility of -OH to a bonding involving the electrons of the phenyl ring. The Ads obtained in this work are of the approximate order of magnitude as those observed for the -OH to a bonding in @-phenyl ethanols,16 and the diols measured herein might be considered structural analogs of the P-phenyl ethanols with suitable changes in substitution on the a and P carbons. The possibility of -OH to a bonding in the PhRC(OH)C(OH)RPh series has been tested by employing the known sensitivity of such bonding to the basicity of the acceptor.16,16A tighter hydrogen bond is obtained when electron release into the aromatic system is facilitated. Synthesis and spectral examination of the dl forms of p-methyl and p-methoxyacetophenone pinacols gave Av values of 36 and 35 cm.-’, respectively, and a strong intramolecular bonding peak. Since these values are in perfect agreement with the unsubstituted dl-acetophenone pinacol (see Table I), it appears that bonding between hydroxyls is favored. The diols I, 111, and V can be assigned the dl-configuration, and 11, IV, and VI, the meso. In the case of I and I1 this is in agreement with the results obtained by Cram and Kopecky.’ Experimental The bonding measurements were performed in these laboratories on a Perkin-Elmer 421 grating spectrophotometer and by P. von R. Schleyer of Princeton University on a PerkinElmer Model 21 spectrophotometer with lithium fluoride optics. All diols were examined as dilute solutions in spectral grade carbon tetrachloride according to standard procedures. The diols were prepared according to the procedure in the references noted (see Table I ) and recrystallized to constant melting point. With the exception of the high melting isomer of 4,5-diphenyl4,S-octanediol (VI), all had melting points in agreement with those reported. Diol VI was obtained after several recrystallizations from 1: 1 hexane-benzene as white microneedles of m.p. 128-129’, as reported. Anal. Calcd. for CZOHZ~OZ: C, 80.49; H , 8.78. Found: C, 80.47;H , 8.88. The dl isomer of 2,3-di-p-tolyl-2,3-butanediol was prepared as described by Backer, Stevens, and Van der Bij .I7 The configurational assignments provided by the authors, on the basis of relative oxidation rates with lead tetraacetate, are confirmed by the bonding study. (13) L. P. Kuhn, J . Am. Chem. Soc., 74, 2493 (1952). (14) L. P. Kuhn, ibid., 80, 5950 (1958). (15) P. von R. Schleyer. C. Wintner, D. 9. Trifan, and R. Bacskai, Tetrahedron Letters, 14, 1-7 (1959). (16) M . Oki and H. Iwamura, Bull. Chem. Soc. J a p a n , 89, 1135 (1959). (17) H. J. Backer, W. Stevens, and J. R . Van der Bij, Rec. trau. c h i n . , 69, 1146 (1940).
2155
The dl isomer of 2,3-di-p-anisyl-2,3-butanediol was prepared by a method employing Cram’s rule of asymmetric induction.’ To an ice-cooled solution containing 0.40 mole of p-anisylmagnesium bromide in 700 cc. of anhydrous ether was added 0.10 mole of 2,3-butanedione in 20 cc. of ether. After addition was complete, the mixture was stirred 12 hr. and hydrolyzed with iceammonium chloride solution. The ethereal extracts were concentrated to an oil and steam distilled to remove unchanged diketone and other volatiles. The organic portion of the nonvolatiles was dried and chromatographed on alumina with hexanebenzene elutants. A total of 7.1 g. (23%) of the dl-diol was obtained, m.p. 122-123’, (lit.I8 m.p. 122-123’).
Acknowledgment.-Appreciation
is expressed to Dr.
P. von R. Schleyer, Princeton University, for confirming a portion of the bonding measurements and suggesting the possibility of -OH to a bonding and to Dr. Harold C. Beachell, this institution, for helpful discussions and interpretation. (18) C. C. Price and G . P. Mueller, J . A m . Chem. Soc., 66, 634 (1944).
Preparation of 2-Bromopyrimidines HENRYB A D E RAND ~ NORMAN SPIERE Division of Organic Chemistry, Ortho Research Foundation, Raritan, New Jersey Received January 88, 1963
Conversion of 2-amino- to 2-chloropyrimidines is usually effected by diazotization in concentrated hydrochloric acid. The yields by this procedure rarely exceed 30700.2 Alternatively, the amine may be diazotized in the presence of sulfuric acid, giving the 2hydroxy compound which subsequently is chlorinated with phosphorus oxychloride; the over-all yield in this process is likewise about 30%. In our own experience, application of the first method to 2-amin0-4~5-diethoxypyrimidine gave the 2-chloro derivative in 38% yield. We have observed that significantly better results can be obtained in the analogous preparation of 2bromopyrimidines, by diazotization in hydrobromic acid after formation of a perbromide. This method, introduced by CraigS for application to 2-aminopyridines, seems not to have been used hitherto in the pyrimidine series. Thus, 2-amin0-4~5-diethoxypyrimidine gave 2-brom0-4~5-diethoxypyrimidinein 79% yield, and 2-amino-4-chloro-5-ethoxypyrimidinegave 2-bromo4-chloro-5-ethoxypyrimidine in 67% yield. However, the utility of this reaction is circumscribed by the possibility of side reactions; in particular, it appears that the ease of electrophilic 5-bromination of the pyrimidine ringla will limit the use of the Craig reaction to 5-substituted pyrimidines. From 2amino-4-methoxypyrimidine the major product was 2(1) American Cyanamld Company, Bound Brook, N. J. (2) (a) N. Sperber, D. Papa, E . Schwenk, M . Sherlock, and R . Fricano, J. A m . Chem. Soc., 7 8 , 5752 (1951), reported a 52% yield of Z-chloropyrimidine from 2-aminopyrimidine; however, (b) I. C. Kogon, R. Minin, and C. G . Overberger, O w . Sun.,86, 34 (1955), obtained yields of only 2627% in this same preparation; (0) K. L. Howard, U. S. Patent 2,477,409 (July 26, 1949), quotes only one yield, 26.8% in the conversion of 2-amino-5chloropyrimidine to 2,5-dichloropyrimidlne. (3) L. C. Craig, J . A m . Chem. Soc., 66, 231 (1934). (4) (a) G. W. Kenner and Sir A. Todd in R. C. Elderfield, “Heterocyclic Compounds,” Vol. VI, John Wiley and Sons, Inc., New York, N. Y.,1957, PP. 290-295; (b) p. 301.
NOTES
2156
amino-4-methoxy-5-bromopyrimidine(25%), together with 2,5-dibromo-4-methoxypyrimidine(19yo). Under the same conditions, the only product isolable from 2aminopyrimidine itself was 2% of 2-amino-5-bromopyrimidine.5 The low yield of recognizable products in the latter case indicated that some side reaction other than ring bromination also was taking place. In a few other instances, such as 2-amino4,5-di-n-propylpyrimidine and 2-amino4-chloro-5-n-propylpyrimidine, the desired product was obtained in only about 10% yield. The principal products from these reactions, which could not be purified, were bromine-containing solids insoluble both in nonpolar solvents and in water. Since they showed no absorption maxima in the ultraviolet, it may be conjectured that degradation of the pyrimidine ring had occurred. In all the bromopyrimidines described, the position of the bromine atoms was verified by attempted displacement with sodium methoxide. As is well known, halogen substituents in the 2-, 4-, and 6-positions undergo ready nucleophilic displacement, whereas those in position 5 are resistant to such a t t a ~ k s . ~ bIn conformity with expectations, 2-amino-5-bromopyrimidine and 2-amino-4-methoxy-5-bromopyrimidinewere recovered unchanged, and 2,5-dibromo-4-methoxypyrimidine underwent selective displacement of the 2-bromine atom to give 2,4-dimethoxy-5-bromopyrimidine. It may be worth noting that, in 2-bromo-4-chloro-5ethoxypyrimidine, the 4-chloro substituent proved to be more susceptible to nucleophilic attack than the bromine in position 2. With one equivalent of sodium ethoxide, it was converted in 95% yield to 2-bromo4,5-diethoxypyrimidine. (With excess sodium ethoxide, both halogen atoms were replaced, giving of 2,4,5triethoxypyriniidine. ) Experimental
2-Bromo-4,5-diethoxypyrimidine.-To a suspension of 20.2 g. (0.11 mole) of 2-amino-4,5-diethoxypyrimidinee in 55 ml. of 48% hydrobromic acid, 16.9 ml. (0.32mole) of bromine was added a t O', with stirring, over a period of 45 min. During this addition, the mixture became very thick, but subsequently thinned out again. A solution of 19.4 g. (0.28mole) of sodium nitrite in 28 ml. of water was added, still a t O " , over a 30-min. period and the stirring was continued for an additional 30 min. The resulting dark solution was cooled to -lo", and 200 ml. of a 2070 solution of sodium hydroxide was added until a permanent basic reaction was produced. Filtration yielded 21.5 g. (79.0%) of 2-brom0-4,B-diethoxypyrimidineas a pale yellow solid, m.p. 49', which crystallized from pentane without change in melting point. A,nal. Calcd. for CsHllBrN202: C, 38.88; H, 4.49. Found: C, 38.61; H , 4.48. The hydrochloride, prepared with ethereal hydrogen chloride, melted a t 135'; after softening, 95'. Anal. Calcd. for CsH12BrC1N202: C, 33.88; H, 4.27. Found: C, 34.29; H, 4.45%. 2-Bromo-4-chloro-5-ethoxypyrimidine.-Under the same conditions, except that the product was isolated by extraction with methylene dichloride, 2-amino-4-chloro-5-ethoxypyrimidinee gave a 67% yield of 2-bromo-4-chloro-5-ethoxypyrimidine, m.p. 4346", after recrystallization from hexane. (5) After this work was completed D . D. Bly and M. G. Mellon reported [J. O r g . Chem., 87, 2945 (1962)l conversion of 5-aminopyrimidine to 2bromopyrimidine in a 26.67, yield by "reverse addition" diazotization. The scope of this method has not been establirrhed. It may be complementary in its application to the method described in the present paper. (6) W. Braker, E. J. Pribyl, J. T . Sheehan, E. R . Spitzmiller, and W. A . Lott. J . A m . Chem. Soc.. 69, 3072 (1947).
VOL.28
Anal. Calcd. for CeHeBrC1N20z: C, 30.35; H, 2.55; N, 11.80. Found: C, 30.65; H , 2.57; N, 11.80. 2-Bromo-4-chloro-5-n-propylpyrimidine.-Diazotization of 3.8 g. (0.0163 mole) of 2-amino-4-chloro-5-n-propylpyrimidine (prepared via 5-n-propylisocytosine, m.p. 236", by the method reported for 2-amino-4-chloro-5-methylpyrimidine7;m.p. 168") and work-up in the same manner described gave, after concentration of the methylene dichloride extract, a residue which was extracted with pentane. Distillation of the pentane extract yielded 0.35g. (9.3%) of 2-bromo-4-chloro-5-n-propylpyrimidine, b.p. 130" (18 mm.), ~ Z Z D 1.5475. Anal. Calcd. for C7H8BrClN2: C, 35.69; H , 3.42. Found: C, 35.66; H, 3.74. The pentane-insoluble residue was recrystallized several times from isopropyl alcohol, yielding 0.98 g. of a solid, m.p. 226227",which failed to give a good analysis. 2-Amino-4-methoxy-5-bromopyrimidine.-Twenty-fivegrams (0.2 mole) of 2-amino-4-methoxypyrimidine was subjected to the Craig bromination procedure, the reaction mixture was extracted with ether, and the extracts evaporated to dryness. The residue was extracted with hot hexane, and the solution concentrated to a volume of 150 ml. A 10.0-g. sample (24.5%) of 2-amino-5-bromo-4-methoxypyriniidine,separated as pale yellow prisms, m.p. 118'; lit.8 m.p. 125-126". Anal. Calcd. for CsHeBrlu'aO: C, 29.43; H, 2.96; Br, 39.17; PI;, 20.59. Found: C, 29.58; H , 2.93; Br, 38.88; N, 20.12. 2,5-Dibromo-4-methoxypyrimidine .-The hexane mother liquor was washed with 10% aqueous hydrochloric acid (to remove remaining traces of starting material), then dried, and concentrated. A 10.4-g. sample (19.4%) of 2,5-dibromo-4-methoxypyrimidine crystallized as colorless needles, m.p. 85'. Anal. Calcd. for CsH4Br2N20: C, 22.41; H , 1.50; Br, 59.66. Found: C, 22.83; H , 1.50; Br, 59.72. 2-Amino-5-bromopyrimidine.-Treatment of 23.5 g. of 2aminopyrimidine with bromine and nitrite in the same manner described gave, after ether extraction of the reaction mixture, a residue of 0.7 g. (1.7%) of 2-amino-5-bromopyrimidine as light yellow plates, m.p. 235' (after softening), which crystallized from methanol in long needles; lit. m.p. 242-244'9 and 235-237".'0 Anal. Calcd. for C4H4BrN3: C, 27.61; H , 2.32; Br, 45.93. Found: C, 27.33; H , 2.35; Br, 46.20. Reaction of 2-Bromo-4-chloro-5-ethoxypyrimidine with Sodium Ethoxide. (A) 2-Bromo-4,5-diethoxypyrimidine.-A solution of 16.5 g. (0.0695mole) of the pyrimidine in 50 ml. of ethanol was added a t 0' to a solution of 1.6 g. (0.0695g.-atom) of sodium in 50 ml. of ethanol. The mixture was heated under reflux for 2 hr., filtered, and concentrated in vacuo. To the residue a small amount of water was added and the mixture extracted with pentane. From the extract 16.3 g. (957'0 yield) of 2-bromo-4,5diethoxypyrimidine, m.p. 48', was obtained. (B) 2,4,5-Triethoxypyrimidine.-In the same way, 22.9 g. (0.0965 mole) of the pyrimidine and 6.7 g. (0.29 g.-atom) of sodium in 150 ml. of ethanol gave 17.9 g. (95%) of 2,4,5-triethoxypyrimidine, as a pale yellow solid, m.p. 33-34', b.p. 147' (15 mm.), solidifying to a colorless solid, m.p. 35.5'. Anal. Calcd. for CloHleN203: C, 56.58; H, 7.60. Found: C, 56.81; H , 7.72. The hvdrochloride, DreDared in ethereal hvdrogen chloride " _ solution, crystallized in busters of needles, m.p. 104". Anal. Calcd. for CIoH17CIN2Oa: C, 48.28; H , 6.89; N, 11.27. Found: C, 48.32; H , 6.60; N, 11.13. The same triethoxypyrimidine was obtained in 84% yield from 2-bromo-4,5-diethoxypyrimidineand sodium ethoxide. S-Bromo-2,4-dimethoxypyrimidine.-A solution of 2.0 g. (0.00747mole) of 2,5-dibromo-4-methoxypyrimidineand 0.44 g. of sodium methoxide in 50 ml. of methanol was heated under reflux for 16 hr., then evaporated to dryness. The residue was treated with water and extracted with methylene dichloride. The dried extract gave, on vacuum distillation, 0.8 g. (50%) of oil, b.p. 125' (17mm.), which crystallized a8 colorless plates, Hilbert and Jansen" recorded the compound as m.p. 51-52'. prisms, m.p. 63-64'. (7) R. Hull, B . J . Lovell, H . T . Openshaw. and A. R . Todd, J. Chem. Soc., 41 (1947). ( 8 ) J. P. Englirrh, J. H. Clark, R . G. Shepherd, H. W. Marson. J. Krapcho, and R . 0 . Roblin, J. A m . Chem. Soc., 6 8 , 1039 (1946).
(9) J. P . English, J. H. Clark, J. W. Clapp, D . Seegar, and R . H. Ebel, i b i d . , 68, 453 (1946). (10) C. Ziegler, U. S. Patent 2,609,372 (September 2, 1952). (11) G. E . Hilbert and E . F. Jansen, J . Am. Chem. Soc., 66$ 134 (1934).
NOTES
AUGUST,1963 Anal. Calcd. for CBH,BrNPOz: C, 32.89; H, 3.22; Br, 36.48. Found: C, 32.91; H , 3.15; Br, 36.49.
Acknowledgment.-The authors are grateful to M r . Joseph Grodsky and Mr. Charles N. Harper for the elemental analyses.
Studies on Sphingolipids. VIII. Separation of the Diastereoisomeric Dihydrosphingosines. A Simplified Synthesis' DAVIDSHAPIRO A N D TUVIA SHERADSKY Daniel Sie$ Research Institute, The Weizmann Znstitute of Science, Rehovoth, Israel Received March 6 , 196s
NIost syntheses of dihydrosphingosine lead to a mixture of the two possible diastereoisomers,2-6whose separation is difficult to achieve. In the course of a recent investigation we observed that pure erythro-E-dichloroacetyldihydrosphingosine crystallized from the crude mixture and could thus be separated from its steric counterpart. In a previous report7 we described a synthesis of dihydrosphingosine which involved reductive acetylation of the phenylhydrazone I and a selective reduction of the resulting ethyl 2-acetamido-3-oxooctadecanoate with lithium aluminum hydride to give X-acetyldihydrosphingosine. While deacetylation proceeded satisfactorily when run on a relatively small scale, we experienced difficulties with the preparation of larger quantities of dihydrosphingosine, since considerable amounts of the amide resisted hydrolysis even after prolonged reaction. Reduction of phenylhydrazones of type I with zinc and acetic acid usually is effected in the presence of acetic anhydride with formation of an acetamido g r ~ u p . ~ -We ~ have found that acetylation can be avoided by employing moist acetic acid, and we were able to isolate the keto ester I1 as the hydrochloride in 89% yield. The same result was achieved with formic acid a t a slightly elevated temperature. Zn/AcOH
R--CO--C--COOC2H,
ll
or HCOOH
R-CO-CH-COOCIHI
I-+
N--NH--CsHs
NHsCl-
I
I1
2157
aluminum hydride was treated directly with methyl dichloroacetate1° and pure erythro-N-dichloroacetyldihydrosphingosine (111)was obtained after one crystallization. Mild alkaline hydrolysis afforded dihydrosphingosine. The present synthesis offers a convenient method for the preparation of dihydrosphingosine in batches of ten to twenty grams. Experimental Ethyl 2-Amino-3-oxooctadecanoate Hydrochloride (11). (A) With Zinc Formic Acid.-To a vigorously stirred suspension of zinc powder (10 g.) in 98% formic acid (100 cc.) the phenylhydrazone I (8.56 g . ) was added in portions, the temperature being maintained a t 45-50'. After the addition was complete, the mixture was stirred for 20 min., cooled, and the zinc filtered off. The filtrate was poured into cold 2 N hydrochloric acid (100 cc.) and the product was filtered, washed with water, and dried. Crystallization from ten volumes of tetrahydrofuran yielded 6.7 g. (89%) of 11, m.p. 126-128" (lit.ll m.p. 114-116'). Anal. Calcd. for CtaH40NOaC1: C, 63.53; H, 10.64; C1, 9.39; N, 3.70. Found: C, 63.30; H , 10.47; C1, 9.27; N, 4.04. (B) With Zinc-Acetic Acid.-A solution of the phenylhydrazone (8.56 9.) in 97% acetic acid (70 cc.) was added during 30 min. to a stirred suspension of zinc powder (10 g.) in 97Oj, acetic acid (30 cc.), the temperature being maintained a t 18-22' by external cooling. After stirring the colorless mixture for 15 min., the zinc was filtered off and the filtrate poured into cold 2 N hydrochloric acid (100 cc .). Crystallization from tetrahydrofuran yielded 6.5-6.7 g. of 11, m.p. 126-128". erythro-N-Dichloroacetyldihydrosphingosine(III).-A solution of the ester hydrochloride I1 (25 g.) in dry tetrahydrofuran (500 cc.) was added to a cold suspension of lithium aluminum hydride (10 9.) in dry tetrahydrofuran (250 cc.). After stirring a t 40' for 1 hr., the mixture was cooled and the excess of lithium aluminum hydride decomposed by ethyl acetate (5 cc.). Sodium potassium tartrate solution ( l O ~ o , ,500 cc.) was then added, followed by 2 N sodium hydroxide solution (50 cc.), and saturated sodium chloride solution (100 cc.). The ethereal extracts were dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue (18 g.), melting a t 60-70°, was dissolved in methyl dichloroacetate (200 cc.) and the solution heated in a boiling water bath for 2 hr. To the slightly cooled mixture petroleum ether (500 cc.) was added and the precipitated product was crystallized from methanol; yield 12 g. (45%); m.p. 142144". Anal. Calcd. for C20H38NOaC12:C, 58.25; H, 9.53; N , 3.40; C1, 17.20. Found: C, 58.50; H, 9.44; N, 3.63; C1, 17.09. Dihydrosphingosine .-N-Dichloroacetyldihydrosphingosine (4.12 g.) was dissolved with slight warming in methanol (360 cc.), N sodium hydroxide solution (40 cc.) was added, and the solution was left overnight a t room temperature. N Acetic acid (40 cc.) was added and the solution was concentrated in vacuo until precipitation set in. Crystallization from chloroform gave 2.45 g. (sa%), m.p. 85-86'. (10) J. Controulis, M. Rebstock. and H. M. Crooks, ibid., 71, 2463 (1949). (11) I. Sallay, F. Dutka, and G . Fodor, Helu. Chim. Acto, 37, 778 (1954).
1. LiAlHd
P R-CH-CH-CHzOH 2. CltCHCOOCHs
d H AH bOCHCl2
R
=
CHs(CHz)id
I11
The crude mixture of isomers resulting from the reduction of the hydrochloride I1 with lithium (1) Supported in p a r t by a grant from Samuel Rothberg of Peoria, Ill. (2) G. I. Gregory and T. Malkin, J . Chem. SOC.,2453 (1951). (3) M . J . Egerton. C. I. Gregory, and T. Malkin, ibid.,2272 (1952). (4) N. Fisher, Chem. I n d . (London), 130 (1952). (5) M. Prostenik and N. StanCev, J. 070.Chem., 18, 59 (1953). (6) E. F. Jenny and C. A. Grob, Helu. Chim. Acta, 36, 1936 (1953). (7) D. Shapiro, H. Segal, and H. M. Flowers, J. A m . Chem. Soc., 80, 2170 (1958). (8) W. A. Bolhofer, ibid., 74, 5459 (1952). (9) D. Shapiro. H. Sepal, a n d H. M. Flowers, ibid., 80, 1194 (1958).
The Aqueous Chemistry of Peroxychloroacetic Acid E. KOUBEKAND JOHN0. EDWARDS Metcalj Research Laboratory, Brown University, Providence 12, Rhode Island Received November 20, 1962
There are several reports in the literature concerning the in situ preparations of substituted peroxyacetic
NOTES
2158 12.5 11.5 10.5 9.5 8.5
*
-
-
5.5 4.5
1
5
10
20
15
Base, ml.
Fig. 1.-A
typical basic titration curve for a sample of peroxychloroacetic acid, temp., 25".
. *.
- 3.
e . .
2. 0
8
3 8 a
0 0
-3.
0
-
0
U L, 0
2 -4.
0
n
3
bo
1 0
-4. m
- 1.0
0.0 log IHC1041.
+ 1.0
Fig. 2.-A plot of the log of the observed first-order rate constant in sec.-* for the hydrolysis of peroxyacetic acid and peroxychloroacetic acid us. the log of the perchloric acid concentration: temp., 19.9"; 0 ,peroxyacetic acid; 0 , peroxychloroacetic acid.
acids,' but there is available little reliable data concerning their isolation or their aqueous chemistry. I n the case of peroxychloroacetic acid, most of these reports are found in the patent literature12except for some early work by Panizzoma He reported the preparation of peroxychloroacetic acid by its distillation (33-34' with decomposition a t 3.5-4.0 mm.) from a mixture of chloroacetic anhydride and hydrogen peroxide in sulfuric acid. We have found it impossible to isolate any peroxy acid by this method. Our analysis4 of the distillate with ceric and iodide ions showed all peroxide present to be hydrogen peroxide. This is consistent with the fact that the vapor pressure reported by Panizzon corresponds to that of hydrogen peroxide (lit.53 . 5 4 . 0 mm. a t 33-34'). Experimental For the preparation of 'peroxychloroacetic acid, a modified version of the method of Panizzona was used. Hydrogen peroxide (1) (a) W. D. Emmons and A. 9. Pagano, J . Am. Chem. Soc., 77, 89 (1955); (b) F . Fichter, A. Fritscher, and P. Muller, Helv. Chim. Acta, 6, 502 (1923). (2) (a) J. D'Ans, German Patent 251,802 (1911); (b) I. G. Farbenindustrie, British Patent 369,716 (1931); (c) A. Grosse. U. S. Patent 2,806,045 (1957); (d) H. Krim, U. S. Patent 2,813,896 (1957). (3) L. Panizson, H e h . Chim. Acta, 16, 1187 (1932). (4) F. P. Greeuspan and D. G. MacKeller, Anal. Chem., 20, 1061 (1948). (5) W. C. Schumb, C. N. Satterfield, and R. L. Wentworth, "Hydrogen Peroxide," Reinhold Publishing Corp., New York, N . Y.. 1955, p. 226.
VOL. 28
(11.5 g. of 307, B&A reagent) was added dropwise over a period of 1 hr. to 70 g. of concentrated sulfuric acid which was immersed in an ice bath. Then 9.2 g. of chloroacetic anhydride (or 9.5 g. of chloroacetic acid) was added slowly and the resulting mixture stirred until all solid material was dissolved. The resulting clear solution was then allowed to stand for 24 hr. a t room temperature after which it was extracted with three 30-ml. portions of anhydrous redistilled dichloromethane. The extracts were combined and the dichloromethane removed by evaporation under reduced pressure a t 0'; precautions were taken to exclude moisture. A clear viscous liquid ( 3 to 4 ml.) remained after the removal of dichloromethane. Analysis4 of the liquid showed it to contain 5&6070 peroxychloroacetic acid, 1-5% hydrogen peroxide, and 40-5070 chloroacetic acid. The per cent amount of the last compound was established from basic titration curves obtained using a Beckman Model G pH meter. For the hydrolysis experiments 0.5 to 1 ml. of a freshly prepared sample of the last material was added to 50 ml. of perchloric acid solutions, varying in concentration from 0.1 to 11.6 M . These perchloric acid solutions were prepared by direct dilution of 72Y0 perchloric acid (B&A reagent grade) with deionized water. The rates of hydrolysis were studied a t 0, 25, and 35O, constant temperatures being maintained by means of ice and/or water baths. Care was exercised ta eliminate possible errors due to trace metal-catalyzed decomposition. Peroxyacetic acid was prepared by a method analogous to that used for the preparation of peroxychloroacetic acid, except that in this case the peroxy acid could be distilled from the reaction mixture under reduced pressure (30.5 f 0.5' a t 26 mm.). The distillate contained about 70% peroxyacetic acid, 25% acetic acid, and 5% hydrogen peroxide. In this case, as also in the case of peroxychloroacetic acid, the parent acid and the small amount of hydrogen peroxide were found to have little effect on the hydrolysis reaction, the kinetics of which are being reported now. Measurements of the rate of oxidation of nitrosobenzene were carried out in 47% ethanol-water mixtures in a temperaturecontrolled Beckman DK-1 recording spectrophotometer with 1cm. cells. These experiments were conducted under pseudo firstorder conditions, 0,101 M nitrosobenzene being oxidized by 0.100.15 M peroxy acid.
Results and Discussion Fig. 1 shows a typical curve of pH us. milliliters of base added obtained for samples of peroxychloroacetic acid. Although active decomposition of the peroxy acid takes place a t pH values near the pKa, with rapid measurement a reproducible pK, value of 7.2 was obtained. Thus peroxychloroacetic acid is the strongest peroxy acid known to exist in aqueous solution (with the possible exception of peroxyformic acid16for which a pKa value has been measured). It map be pointed out that peroxy acids are known to undergo decomposition in aqueous solution by two pathways other than hydrolysis. These are (1) spontaneous decomposition in aqueous alkaline medialma and (2) trace metal ion-catalyzed d e c o m p o s i t i ~ n . ~During ,~~ the spontaneous decomposition of peroxyacetic acid, oxygen is evolved, while the trace metal ion-catalyzed decomposition is accompanied by the evolution of oxygen, carbon dioxide, and traces of carbon monoxide.'O However, during the hydrolysis of peroxyacetic and peroxychloroacetic acid no gaseous products were ob(6) P. A. Giguere and A. W. Olmos, Can. J . Chem., 80, 821 (1952). (7) (a) D. L. Ball and J. 0. Edwards, J . Am. Chem. Soc., 78, 1125 (1956); (b) J. F. Goodman, P. Robson, and E. R . Wilson, Trana. Paroday Soc., 68, 1846 (1962). (8)E. Koubek, M. L. Haggett, C. J. Battaglia, K. M. Ibne-Rasa, H. Y . Pyun, and J. 0. Edwards, accepted for publication by J . Am. Chem. Soc. (1963). (9) D. L.Ball and J . 0. Edwards, J . Phya. Chem., 62, 343 (1958). (10) E . Koubek and J. 0. Edwards, accepted for publication by J . Inorg. Nucl. Chem. (1963).
AUGUST,1963 served, the only products produced being hydrogen peroxide and the parent acid. Conditions under which each of these three pathways could be studied for the decompositions of peroxyacetic and peroxychloroacetic acid were established. The results of the studies on the spontaneous decompositions and decompositions catalyzed by metal ions are the subjects of separate communications.8lo In view of these facts, during the acid hydrolysis experiments both the kinetics of the disappearance of peroxy acid and the appearance of hydrogen peroxide were studied, KO change in total peroxide content was noticed up to 90% reaction; i.e., the rate of disrtppearance of peroxy acid corresponded exactly to the rate of formation of hydrogen peroxide. Therefore, acid hydrolysis was not accompanied either by decomposition to oxygen or by decomposition to oxygen and carbon dioxide. Both rates (peroxyacetic and peroxychloroacetic acids) appear to follow a first-order relationship (log concentration of peroxy acid us. time gave a linear plot) to goy0 reaction. The results now obtained for first-order rates of hydrolysis of the two peroxy acids as a function of the perchloric acid concentration are given in Fig. 2. The value 0.96 X lW4l./mole sec. for the second-order acid-catalyzed rate constant of peroxyacetic acid agrees with the value of 1.0 X previously obtained by Bunton and co-workers. l1 The rates of hydrolysis were measured at three temperatures (0, 24.8, and 35.3'); the rate constants are listed in Table I. The energies of activation (Ea) calculated from the rate constants given in Table I are 16.8 kcal./mole for the acid-catalyzed hydrolysis of peroxyacetic acid and 13.7 kcal./mole for the uncatalyzed hydrolysis of peroxychloroacetic acid. The entropies of activation (AS*) are -22.6 cal./deg. mole and -29.3 cal./deg. mole in the same order. Experiments to determine the effect of ionic strength upon the hydrolysis rate proved rather unsatisfactory, for the addition of sodium perchlorate led to a rapid decrease in total peroxide content. Most likely this resulted from addition of trace amounts of catalytic ions contained in the perchlorate salt. The rates of hydrolysis of the two peroxy acids can be discussed in terms of the over-all rate law, rate = ko[ROOH] AH [ROOHI [Hd)+]. From the apparent first-order dependence of the rate of hydrolysis of peroxyacetic acid on perchloric acid concentration, it is likely, as Bunton has pointed out, that, the hydrolysis proceeds via nucleophilic attack by water on the unprotonated form. Nevertheless, the constant ko must be less than 5 X lopRset.-' and thus in 1 M acid the uncatalyzed rate amounts to less than 5% of the total rate of hydrolysis. It is seen from Fig. 2 that, in the hydrolyses of the chloro substituted peroxy acid, the uncatalyzed rate is predominant over most of the acidity range, the value sec.-l. Thus the uncatalyzed of ko being 7 X hydrolysis rate is much more significant than the acidcatalyzed hydrolysis over most of the acid range. However, at 8 M perchloric acid, the acid-catalyzed rate begins to contribute significantly to the over-all observed rate as demonstrated by the sharp increase in kobsd. This behavior is not completely unexpected
+
(11) C. A. Bunton, T. A. Lewia, and D. R . Llewellyn, J . Chem. Soc., 1228 (1958).
NOTES
2159
TABLEI THE OBSERVEDFIRST-ORDER RATE CONSTANTS FOR THE HYDROLYSIS O F PEROXYACETIC A N D PEROXYCHLOROACETIC ACIDSAT VARIOUSTEMPERATURES A N D AT VARIOUSCONCENTRAT~OUS O F PERCHLORIC ACID Peroxyacetic acid [HClO,]
0.10 0.50 1.00 2.00 3.00 4 :OO 5.00 6.00 7.00 8.00
24.8O
koba (set.-')--35.30 00
...
1.56 X 5 . 5 6 x 10-6 Y.65 X 1 . 7 8 x 10-4 2 . 6 5 x 10-4
2 . 5 4 x 10-4 4 . 7 5 x 10-4 7 . 0 5 X lo-'
3.42 X 4.43 x 10-4 5.38 lo-'
... . . . .
6.16 7.56
...
x
x x
10-4 lo-'
5.85 x 6.23 x 6.84 x 6.66 X 7.24 X 7.05 x 6.90 x 6.48 X 6.65 x 6.70 x
10-4 10-4 10-4
--
...
...
2 96 X 103 43 x lo-' 4 82 x 10-6
Peroxychloroacetic acid
0.50 1 .00 1.50 2.00 3.00 4 00
5.00 6.00 7.00 9.00 10.0 11.6
. . 1 . 3 3 x 10-8 8 3 5 x 10
6
...
1.58x 10-3 8 70 13-4 1 . 6 4 x 10-3 8 i o 10-4 1.70 x 10-3 9 01 10-4 ... lo-' ... 10-4 . . 10-4 . . 8.35 x 10-4 13 X lo-' (initial rate)
x x x
10-1 10 -&
lo-'
since the chlorine atom, while increasing the positive character of the carbonyl carbon, decreases the basicity of the carbonyl oxygen. Therefore, even though the protonated peroxychloroacetic acid is more susceptible to nucleophilic attack, its equilibrium concentration is much lower (relative to peroxyacetic acid under the same conditions) , these two effects acting in opposition to each other. Tornmila and Hinshelwood,12 in their studies on the acid-catalyzed hydrolysis of benzoic acid esters, found that substituents on the benzene ring had virtually no influence on the rate of reaction; i . e . , kif was found to be essentially the same for the variously substituted benzoic acid esters. Presumably the substituents exert electronic effects similar to those suggested for the chlorine atom in the peroxychloroacetic acid. In order to test the kinetic reactivity of peroxychloroacetic acid as an electrophile, the rate of oxidation of nitrosobenzene to nitrobenzene has been measured along with comparative data for two known peroxy acids. The second-order rate constants for the oxidation of nitrosobenzene at 30' were found to be 5.15 X 35 X lop4,and 167 X l./mole sec. for peroxyacetic,13peroxymono*ulfuric, and peroxychloroacetic acid, respectively. The main disadvantages associated with this new peroxy acid appear to be the ease with which it is hydrolyzed into chloroacetic acid and hydrogen peroxide and its spontaneous decomposition8 into chloroacetic acid and oxygen. The former is prevalent at all ranges of pH while the latter is significant near the pK, (12) E. Tommila and C. N. Hinshelwood. rbid., 1807 (1938). (13) K. M. Ibne-Rasa, C . G. Lsuro, and J. 0 . Edwards, J . Am. Chcm. Soc., 86, 1185 (1983).
NOTES
2 160
of the peroxy acid. In the case of peroxychloroacetic acid both processes take place a t a much greater rate than with peroxyacetic acid. Acknowledgment.-The authors wish to thank the U. S. Atomic Energy Commission for financing part of this work (contract AEC-1983). They also thank Dr. Khairat M. Ibne-Rasa for many helpful discussions and Miss Nan L. Sorensen for technical assistance.
2,3-Dihydro-4H-1,3-benzothiazinones-4 BERNARD LOEV Smith Kline and French Laboratories, Research and Development Division, Philadelphia 1, Pennsylvania Received February 4 , 1968
The only references to the synthesis of 4H-1,3-benzo thiazinones utilize the reaction of thiosalicylamide with aldehydes' or benzal chloride.2
+ p-Cl-CkH4-CHO COOH
+ MeNH,
-
VOL.
28
We have found that 2-phenyl-3-alkyl-dihydrobenzothiazinones are readily prepared from thiosalicyclic acid, an aldehyde, and a primary amine in refluxing benzene. Oxidation by permanganate in acetic acid gives the sulfone. When methylamine was replaced by 1,l-dimethylhydrazine or by aniline, the reaction failed. Experimental8
2,3-Dihydro-J-methyl-2-( p-chlorophenyl)-4H-l,J-benzothiazinone-4-p-Chlorobenzaldehyde (10.0 g., 0.071 mole) was mixed with 30 ml. of anhydrous benzene previously saturated with methylamine. After 5 min. the solution turned milky. The solution was refluxed and water was removed azeotropically ; the theoretical amount of water was obtained in 1 hr. The solution was cooled, powdered thiosalicyclic acid (0.071 mole) was added, and reflux was continued until another equivalent of water was removed (several hours). After cooling, the solution was rinsed with dilute base, dried, and the solvent was then removed. The residual viscous oil snon crystallized. The solid was triturated with hexane then recrystallized from benzene-isopropyl ether (11.0g.,m.p. 123.S124O). Anal. Calcd. for Cl5H12C1NOS: C, 62.17; H, 4.17. Found: C, 62.17; H, 4.08. 2,3-Dihydro-3-methyl-2-( p-chlorophenyl)-4H-1,3-benzothiazin&one 1,l-dioxide.-An aqueous solution containing 8.3 g. (0.053 mole) potassium permanganate was added portionwise, with stirring, to a solution of 9.0 g. (0.031 mole) of the thiazinone in 90 ml. of acetic acid. Slight cooling was required to keep the temperature below 35". The brown mixture containing a tan suspended solid was stirred an additional half hour and a small amount of sodium hydrosulfite was then added to decolorize the solution. The tan solid product was filtered and recrystallized from alcohol-acetone giving 5.5 g. of white crystals (m.p. 169170").
Anal. Calcd. for C16Hl&1N03S: C, 55.99; H, 3.76. Found: C, 55.69; H, 3.87. (1) H. Bohme and W. Schmidt, Arch. Pharm., 186, 330 (1953). ( 2 ) R . Boudet, Bull. soc. chim. France, 1518 (1955).
(3) All melting points are corrected. Analyses were performed by D Rolaton and her staff of these laboratories.
