4354
EDWARD
M. KOSOWER AND
90% dioxane (9 vol. dioxane: 1 vol. water) and kept at 25' for 402 hours (ca. 8 half-lives). Filtration and drying of the long needles which separated gave 200.1 mg. of material, m.p. 150-152", mixed m . p . with cholesteryl trichloroacetate, 151-153 O The filtrate was diluted with 600 cc. of water, and extracted with 200 cc. of redistilled pentane. The pentane extract was washed three times with water anti dried over magnesium sulfate. The solvent was evaporated 011 the steam-bath. An appreciable amount of dioxane remaining was removed at the oil pump through a Dry Ice trap. The oily residue was dissolved in a small volume of redistilled Skellysolve F and chromatographed through a 20-g. column of stock alumina. Using Skellysolve F (F), benzene (B), ether ( E ) and ethanol ( E t ) for elution, the following fractions were collected: (1) 60 ml. F, 60 mg. of residue insoluble in acetone; (2) 75 ml. F, no residue; (3) 40 ml. F, no residue; (4) 60 ml. 1 : l F:B, 149.2 mg. oily residue, crystallized on addition and then evaporation of acetone, m.p. 69.7-71.5', mixed m.p. with 6P-alcohol 69-72" ; ( 5 ) 50 ml. 1: 1 F : B, 115.1 mg. oil which behaved like fraction 4; ( 6 ) 50 ml. 1 : l F : B , 76.8 mg. oil which behaved like fraction 5; (7) 60 ml. 1:l F : B , 35.3 mg. oil, m.p. after acetone tteatment 68.5-70.5', mixed m.p. with 6P-alcohol 68.6-70.9 ; (8) 50 ml. 1 : l F : B , 17.4 mg. oil; (9) 50 ml. 1 : l F : B , 6.4 mg. oil; (10) 80 ml. E, 163 mg. solid, 145 nig. of which gave 497.3 mg. of digitonide and 17.4 mg. of oil recovered from the filtrate from the digitonide preparation (attempted preparation of p-nitrobenzoate from this oil failed); (11) 30 ml. E, no residue; (12) 70 ml. 2 . 5 : l E : E t ,
Vol. 78
34.6 mg. oil which failed to give a p-nitrobenzonte; 75 ml. 2.5: 1 E : Et, no residue. The run may be summarized (in mg.)
.
[CONTRIBUTION FROM THE
s. WINSTEIN
Fr.
Pre. I 2-3 4-9 10 11
12 13
Unident
6@OH
3pOH
(13)
38-OTCA
200 1 tiu
-100 , 1
28
135
34.6
In the other hydrolyses, the alcohols isolated were usually quite pure. Typically, 60-alcohol from runs 9 and 12, Table VI, had m.p. 66-67' and 65-67', respectively, as compared with 67-68" found for pure freshly crystallized 6p-alcohol. It was also shown t h a t 6p- and 3P-alcohols could be separated quantitatively from one another. Thus, a mixture containing 691 mg. of 6P-alcohol and 507 mg. of 3/3-alcohol was chromatographed on 25 g. of alumina. Pentane: benzene (2: 1) eluted the 6g-alcohol, 693 mg. (100%), of which 679 (98%) had m.p. 73-74' arid mixed m.p. the same. With ether, there was eluted 505 mg. (100%) of cholesterol, m.p. 146-147", n1.p. undepressed by authentic cholesterol. Los ANGELES24. CALIFORNIA
DEPARTMENT OF CHEMISTRY OF
THE UNIVERSITY OF CALIFORNIA AT L O S ANGELES]
Neighboring Carbon and Hydrogen. XXIII. Homoallylic Systems. 3,5-Cyclocholestan-6~-ylChloride' BY EDWARD M. KOSOWER~ AND S. WINSTEIN RECEIVED MARCH 19, 1956 By taking advantage of the reactivity associated with the i-steryl structure in ionization reactions and the mediating action of the solvent ether upon hydrogen chloride, 3,5-cyclocholestan-6~-yl chloride has been prepared from 3,5-cyclocholestan-68-01 and thionyl chloride. The structure and configuration of the "i-cholesteryl" chloride are clear from elementary analysis, molecular rotation and chemical behavior. Hydrolysis of the chloride in 90% dioxane gives rise mainly t o 3,5-cyclocholestan-6~-ol and partly t o cholesterol. Also, ion pair return, leading t o cholesteryl chloride, is more important chloride than the trichloroacetate. in hydrolysis of the 3,5-cyclocholestan-6~-yl
x I
I1
I11
In order to compare the behavior of 3,5-cyclocholestan-G-yl derivatives I with cholest-5-en3p-yl derivatives I1 in solvolytic reactions, it was desirable to have isomeric compounds. Although all three trichloroacetates had been prepared successfully, a cholesteryl trichloroacetate had been found3to solvolyze with acyl-oxygen, rather than alkyl-oxygen cleavage. Previous evidence, as well as preliminary experiments, had indicated that the p-toluenesulfonate esters in the 3,5-cyclo series were too reactive. However, WagnerJauregg and Werner4 had shown some years ago that cholesteryl chloride solvolyzes to give products (1) Abstracted from part of Ph.D. Thesis of E . Kosower, UCLA, 1952. (2) Research Fellow of the National Institutes of Health, 19491952. (3) E. M. Kosower and S. Winstein, THISJOURNAL, 78, 4347 (1956). (4) T. Wagner-Jauregg and L. Werner, Z,p k y s i o l . Ckem., 213, 119 (1932).
now ascribed to 5,G-doublebond participation with formation of hybrid ion III.3 Therefore, the 3,5cyclocholestan-6-yl chlorides were of interest for comparison with cholesteryl chloride. Tn this paper is reported a study of the preparation and hydrolysis of 3,5-cyclocholestan-f/?-yl chloride. Preparation and Behavior of "i-Cholesteryl" Chloride.-A statement that the chloride could not be prepared has appeared.6 However, our experiments with the 3,5-cyclocholestanyl trichloroacetates,J including rate studies,6 suggested that the chloride might be isolable. From the kinetic results6 obtained with the trichloroacetates, it was clear that a 3,5-cyclocholestan-6-yl chloride would display an extremely high rate of ionization and, therefore, be very subject to rearrangement. Thus, successful isolation of such a chloride would depend on precautions in procedure designed to avoid ionizing conditions. For reasons which will be clear from the discussion below, thionyl chloride was used as a reagent on the 3,5-cyclocholestan-G-ols. Ether was employed as a solvent because i t represents a volatile, (5) C W. Shoppee, Bull. soc. ckim., [VI 18, C120 (1951). ( 6 ) E. I v l . Kosower, unpublished work
Sept. 5, 1956
4355
3,5-cYCLOCHOLESTAN-6/3-YL CHLORIDE
inert solvent of low dielectric constant, which is from the 6/3-alcohol. However, there was an inbasic7s8 and moderates the catalytic effect which dication of 10-1570 of another “active chloride” could be expected from hydrogen chloride toward somewhat slower than the predominant one. the rearrangement3 of a 3,5-cyclo chloride. The The “active chloride’’ derived from the 3,5-cyclosame solvent displayed an exceptionally low rate of choIestan-6/3-01 (IV) rearranged readily to cholesisomerization of camphene hydrochloride in the teryl chloride (X), even in chloroform solution. classic investigation of M e e r ~ e i n . ~Also, i t has Thus, the observed optical rotations on various been employed to advantage by W. G. Young and chloride preparations in chloroform decreased in co-workers’O in these laboratories to moderate the less than 24 hours from the initial value to a specific action of hydrogen chloride during the action of rotation of -30’. The specific rotation of cholesthionyl chloride on allylic alcohols. teryl chloride1* is -30’. In carbon tetrachloride Thionyl chloride in slight excess was added to a solution, observed rotations were quite constant. dilute, ice-cold solution of 3,5-cyclocholestan-6/3-ol The fact that the final rotation observed on re(IV) in anhydrous ether. After the addition, the arranging chloride was the value for pure cholesether was evaporated, pentane was added, and the teryl chloride indicated that the inert material in solvent was evaporated. The white residue was the original chloride preparation was also cholesdissolved in dry acetone, and the solution was teryl chloride. This conclusion was verified with cooled to -78’. The white solid which separated the infrared absorption of the chloride preparations. was filtered quickly and dried under vacuum. Cholesteryl chloride displays strong absorption a t This material analyzed correctly for a chloride, 11.43 p , and transmissions a t this wave length are C2,H&1, and it consisted mainly, but not en- correlated well with the silver nitrate analyses for tirely, of chloride which is titratable with silver inactive chloride. This correlation is summarized nitrate under conditions toward which cholesteryl in Table I. chloride is inert. When pyridine was employed in TABLE I the thionyl chloride-3,5-cyclo-alcoholreaction, the INFRAREDABSORPTIONOF CHLORIDES AT 11.43 p chloride product displayed a somewhat lower 7 0 “active chloride” content and seemed less stable on “Active” Yo Transmission (RCI)a RCl Obsd. Calcd. standing. Otherwise, i t did not differ from the 99 83.6 78 79 previous product, even in the kinetic studies.6 96.9 72.4 71 70 98.9 0 27 (27)b a In mg./cc. carbon tetrachloride. Used to calculate the other values.
0
+
ci/s‘o
ax7 V
X
I
iL
y-s . .
VI11
0
CE VI1
The 3,5-cyclocholestan-6a-olyielded less satisfactory results in the reaction with thionyl chloride. Three attempts were made to treat 3,5-cyclocholestan-6a-01 with thionyl chloride, two in the manner described above for the 6/3-alcohol, and the other in a pentane solution of N,N-di-isopropyl-otoluidine.” The latter procedure yielded a white solid which contained a large proportion of “active chloride.’’ Most of the “active chloride” displayed a rate6 of solvolysis identical to that of the chloride
On the assumption that the chloride from 3,scyclocholestan-6/3-ol (IV) contained only one “active chloride” along with the more inert cholesteryl chloride, i t was possible to estimate a specific rotation for the “active chloride.” The estimates of [a]Dfor the “active chloride,” based on initial rotations and cholesteryl chloride contents, are summarized in Table 11. The concordant calculated values obtained for different preparations support the idea of a binary mixture. However, the kineticss of hydrolysis of the chloride, to be reported in a following article, supply more convincing evidence that only one “active chloride” is present in the chloride preparations from 3,5-cyclocholestan6/3-01 (IV). TABLE I1 CALCULATED SPECIFIC ROTATIONS OF “ACTIVE IN CHLOROFORM “Active,, chloride,
%
76.5” 72.4“ 83.6
Initial [ab
+26.1 +24.5 4-27.5 f 2 9 . 2h
[a]Dobsd.
CHLORIDE” [ab “active” calcd.
after 24 hr.
- 29 -30
$43 $45
+41h +43 a Sample prepared with addition of pyridine. (7) (a) H. M. Buswell, W. H. Rodebush and M. F. Roy, THIS carbon tetrachloride solution. JOURNAL, 60, 2528 (1938); (b) D. R . Chesterman, J . Ckem. Soc., 906 (1935). (8) T. M . Mounajed, C o m p f .rend., 197, 44 (1933). (9) H.Meerwein and K . van Emster, Ber., 66, 2500 (1922). (10) W. G.Young, F. Caserio and D. Brandon, Science, 117, 473
(1953). (11) This substance was kindly made available by F. F. Caserio,
Jr.
Av.
In
Structure and Configuration.-That the “active chloride” from 3,5-cyclocholestan-6/3-ol (IV) is a 3,5-cyclocholestan-6-yl derivative is evident from the nature of the hydrolysis products. A sample, , (1948). (12) D.H.R. Barton and J. D Cox, J , Ckem. S O L . 783
EDWARD &I.KOSOWGR AND 8. W I N S T E I N
4356
Vol. 7s
“active,” was hydrolyzed in OOyo dioxane containing excess lithium acetate under conditions toward which cholesteryl chloride is inert. Correcting the products obtained for the cholesteryl chloride present in the starting material, the products derived from the “active chloride” are i2Y0 3,3-cyclocholestan-6p-ol (IV), S% cholesterol (VI 11) and 20% cholesteryl chloride (X). When the solvolysis solution was not buffered, the yield of GP-alcohol IV was only 3y0,and yet only 17% cholesterol (VIIIl was isolated. The remainder of the “active chloride” gave rise to cholesteryl chloride (SOY0). These results are summarized in Table 111. Regarding the configuration of the
tiori for the “active chloride,” + U ” , one obtaiiis an MD of +174 for “active chloride.” The A X D ( A - B) between “active chloride” and cholesteryl chloride is +295”, which is very close to the range of A X D values. The fact that it is slightly below the range and not above is significant; 6a-derivatives invariably have much higher positive rotations than GP-compounds. Thus, molecular rotation data support the designation of the “active chloride” as 3,~-cyclocholestan-r,P-ylchloride (IX). Discussion.-The formation of alkyl chloride from alcohols and thionyl chloride involves intermediate alkyl chlorosulfinates, some of which have been studied directly by Lewis and his students. l9 There are many indications of a tendency on the TABLE111 part of the chlorosulfinates to react in the liquid P R O D U C T S O F sOLVOLYSIS O F 3,5-CYCLOCHOLESTAN-6P-YL phase by way of alkyl-oxygen ionization prior to CHLORIDE IN 90% DIOXANE AT 25” bonding of chlorine to carbon. Pertinent examples (IIcl),a 102 nr 3 1 3 5 occur in the reaction of thionyl chloride with 2(LiOAc), lo2 -%I 14 7 1iiethyl-2-phenyl-l-butan01,~~ the 3-chloro-2-butaTime, hours 38 39 ti01s,*~cyclopropylcarbinolZ2and the 3-phenyl-2Total % recovery 95 94 butan01s,~3 The case of the 3-chloro-2-butanols2~ ( % cholesterol (YIII) 8 17 is very significant, since alkyl-oxygen ionizatioii ’ % 3,5-cyc~ocholestan78 3 precedes chloride attack even though such ionizaProduct {, , 6B-01 (IV) tion is very slow in the presence of a neighboring . . % cholesteryl C1 ( X ) 20h’” sob chlorine atom.24 a 83.6cl, “active chloride.” Corrected for cholesteryl The pronounced tendency toward ionization dischloride content of the starting chloride. 3,s-Cholestadi- played by alkyl chlorosulfinates and the demonene content less than 0.05% 011 the basis of the ultraviolet strated importance in other cases of “internal respectruiii. turn”?jof an ion pair t o the covalent condition sug3,3-cyclocholestan-6-yl chloride from 3,S-cyclocho- gest that ion pair i n t e r i n e d i a t e ~ ~ .occur ’ ” ~ ~ in the Iestan-Gp-ol (IV) one indication comes from solvoly- Ssi mechanism. The latter, presumably by way sis rates.6 The “active chloride” in question is ca. of a 4-ring cyclic transition state, was suggested by I O ‘ tiines as reactive as one component of the Flughes, Ingold and co-morkers’6 to explain converchloride product from the 3,5-cyclocholestan-(ia-o1. sion of chlorosulfinate to chloride with retentioil The factor of ca. 10’ is close to the one observed of config~ration‘~ in certain cases. between the 3,5-cyclocholestan-6P- and Roc- trichloU’hile no rates were measured for the conversion roacetates.6 This suggests that the slower “ac- of 3,5-~yclocholesta1i-~~-ol (IV) to chloride with tive cliloridc” in the product from Goc-alcohol is a thionyl chloride in ether, the formation of chloride Ga-chloride and the “active chloride” from 6P- was obviously very rapid, even a t 0’. On the alcohol is entirely Bp-chloride (IX). Further sup- other hand, 2-butyl chlorosulfinate has a halfport for the GP-assignment to the chloride from lifelgb of two minutes a t 99’. Thus, we estimate a :3,S-cyclocholestan-GP-ol (IV) is obtained from con- niinimuni factor of lo5 between rates of reaction of sideration of molecular rotations. 3,5-cyclocholestan-GP-y1 (V) and 2-butyl chlorosulAs summarized in Table IV, the differences in finates. Such high reactivity for the 3,3-cyclomolecular rotation between a cholesteryl and a 3,5- cholestanyl derivative V is in line with carboncyclocholestan-6P-yl derivative range from 4-31: ’ oxygen ionization, since \cry high rates6 are obto +37S0, depending upon the nature of the iso- served in solvolytic reactions reported in a followmers. From the average calculated specific rota- ing paper. Subsequent to alkyl--oxiygen ionization, collapse of carbonium chlorosulfinate or carTAIKE IL. lioniuni chloride ion pairs V I or VIT, mainly to :3,5~ ~ U I . E C U I . A KR w x r r o s DIE cyclocliolestaii-C,P-yl(IX) and parlly tci cliolesteryl so Coinparison .&/I3 A . \ f l J ( z i - u) (X) chloride, is visualized As i n solvolysis, rc:tcI
1
2 3 -
3,5-c)clr)-C,lj7-OMe/3-en-:~~-O~~~e13~1~~ 3 2 f 22 ( i ’ p 3 , 5 - C ~ c l o - F P - S R ? j ~ - ~ i i - ~ ‘ ~ ~317 - ~ Rf ~ ~375 -( ”3I 3 , 5 - C ~ c l o - G 8 - O H / 5 - e n - : ~ ~ - ~ H ~ *320 ~ l *=k 14 ( 3 )
S u i n l x r o f pairs compared. ~~
(13) ( a ) B. Kiegel, \ I . k’ IA’ Dunker and .\I J . ‘l‘homac, T H I S , 2113 ( 1 9 4 2 ) . ( b ) F’. T.. Julian, E. W Sfeyer and 1 7 2 , 307 (19.70); (c) 11. X f , R a t h m a n n and I.. R . h f < r n J w , ~ b i g i ,72, 3017 ( l 9 5 0 ) . ( I I ) 15 W . XIPyer, 1’li.r). T l i e b i i , Sorthwestertl Unirer>ity, 1!113 (13) P. L Julian, 4 . Maynani, E , W. Meyer a n d IV. Culr, TiiIs
70, 1834 (leis). (16) h1, J. Bigelow, Ph.D. Thesis, Xorthwestern University, 1950. (17) 12. Sorni, I,. L i b l e r , \’ eernj., Chenz. L i d y , 47, 418 ( 1 0 5 3 ) . (18) (a) A . F.\h‘agnrr, S . P;. U‘olff a n d IC. S . Wallis, J . 0i.g. C h e w , 17, 529 (3932); ( b ) A . Uutrnandt, 2 . p h y s i o i . Cheln , 237, 57 (1035), (c) A . Butenandt a n d I,. A . Suransi. B e v . , 75, 591 (1042).
L e w i s and C . 1,:. 13,K,r,cr, ’I‘irls
J u l l ~ h . h l ,74,
308
S. Lewis a n d C. 1C. Boozer, ibid, 75, 3182 (lCl53); f ~ c )C . E . Bnozer and E . S. Lewis, ibid , 7 6 , i 0 1 (19.54); i d ) E . S. T.ewis and V, (20) (21) (22) (231 (21) (1948)
hr. Coppinger, ibid , 7 6 , 796 i l R 5 4 ) 11 S. Wallis and P. I . Bowman, J , O r g Chem , 1, 383 (1036). H . J Liicas a n d i‘.W Could, T H x s J O U R N A L , 63, 2341 (1941). J D . R o h e r t s and R . H. XIazur, i b i d , 73, 2609 (1081). I> J Cr:1n1. ibis/ , 75, 3 3 2 (1023). 5 IVi1151rii,, l i C r i i n u ~ I
