of higher alcohols boiling a t 135-150" obtained from the synthetic methanol process,7 was refluxed for twelve hours. The liquid was decanted from a small amount of solid niaterial (4.5 g . ) and distilled. After removal of the excess alcohols, the carbamate was obtained a t 110-125° under 4 mm. pressure. The product was slightly yellow arid remained liquid a t room temperature. The yield was 137 g. or about 60% of the theoretical. Ethylene Glycol and Urea.---A niisture of 240 g . of urea, 124 g. of ethylene glycol, and 12 g, of glycrrnl yielded a transparent water-soluhle sirup after a heating period of six hours a t 180-163" and four hours a.t 170-175". 'hiethylene Glycol and Urea.--A mixture of 60 g. of urea, 6 g. of glycerol, and 1;10 g. of triethylene glycol was heated at 140-150" for one and one-half hours and slowly increased during eight 11oui-s t o 175". The excess triethylene glycol was removed by distillation and 115 g. (57.8%) of a non-volatile wa.ter soluble sirup obtained. Lpon standing for two weeks, a srnall amount of crystalline material separated which, upon crystallization from acetone, melted at 108' ant1 proved to be the diurethan.
-
._I___
( 7 ) ?'he following compounds have been identified in chis fraction by Graves, I s d . f i x g . C ' h ~ m . ,23, 1381 (1931). 2-methyl-lpentanol, 2,l-dirnethyl 3-pentanol s n d 2.4-diniethyl .I-pentanol.
[CUXTRIBUTION F R n M THE IlABORATORY OF
Anal. Calcd. for CsHlaOsNz: C, 4067; H, 6.77; N.
11.HF. Found: C, 4087, H, 6 6 6 ; N, 11.32. Sorbitol and Urea.- Resins of varying viscosity were ohtained depending upon the ratio of urea to sorbitol Pure compounds could not be isolated.
Summary n-Dodecyl carbamate, octyl carbamate, isobutyl carbamate, and the mixed carbamates from one fraction (b. p. 135-150') of the higher alcohols obtained in the methanol synthesis have been prepared by the reaction of urea with the corresponding alcohols at atmospheric pressurc. A ttempts t o obtain alkyl carbonates by the same procedure were unsucsesslul. Polyhydric alcohols reacted with urea under the same conditions to yield sirups from which pure compounds could not be isolated except in the case of triethylene glycol. The latter yielded a sirup from which a small amount of the ditirethan of m. p. 108' was obtained. [VI1 M I N G l r ) N , 1)Ll.AWARE;
BIOLOGICAL CHEMISTRY,
f k H O O L OF
RECEIVEDMAY13, 1838
MEDICINE, UNIVERSIfY
OF
BUFFAL,O 1
A Critical Examination of the Reaction of Iodine Monobromide with Cholestenone and p-Cholestanone BY J. 0. RALLS In a previous study,' it was shown that cholestenone was one of the products of the reaction of iodine monobronlide with cholesterol. I t was also shown that cholestenone behaved toward halogen in a manner that was then considered "abnormal." In addition, Copping2 had stated that cholestenone did not yield analytically correct iodine numbers when Dam's" suggested application of the Rosenmund and Kuhnhenn4 method was used. We were interested, therefore, in attempting to ascertaill the causes of this peculiarity. Inasmuch as A4,5-cholestenone,commonly called cholestennne (suggested name, coprostenone),jcontains a double bond and a ketone group (in a conjugated system), the problem was one of attempting to evaluate, the role of each in the reaction of cholestenone with iodine monobro-
mide. Cholestanone, which contains no double bond, and cholestanoxime, which contains neither the double bond nor the ketone group, served to evaluate the effect of the carbonyl group; while cholestenoxime, which does not contain the ketone group but still possesses the double bond, was used in attempting to evaluate the role of the latter group. In the course of the experimentation, hydrogen bromide catalysis of halogenation was investigated, as was, also, the effect of the oximino hydroxyl upon the halogenation of the ethylene group in cholestenoxime. In the latter work, the factors of solvent nature, of air (oxygen) inhibition, and of the configuration of the oxime were considered. In these studies, syn-styrylphenylketoxime, 3,5-diphenylisoxazol, and 3,5-diphenylisoxazoliiie were also used.
(1) Ralls, THISJOURNAL, 55, 2083 (1933) ( 2 ) Copping, Btochem J , BB, 1142 (1928) (3) Dam Riochem 2 ,182, 101 (1924) ( 4 ) I; It' Rownmund and W Kuhnhenn, Z L'nlersi~ch Anhv i~ (.fw i s s m , 46, 154 9 (1423) 3, 30 (lOJ4) ( I ) 0 Rosenheim dud €I k i n g , '4tt7t Reo BhucIicvi
Discussion and Results The peculiarities of the reaction of cholestenone with iodine monohromide (Curves 1, Fig. 1) are especially evident in the graph of thc organic
Aug., 1938
IODINE MONOBROMIDE ON CHOLESTENONE A N D /3-CHOLESTANONE
1745
halogen. There appears to be some autocatalysis, but it is not simple. Inasmuch as cholestenone contains both a double bond and a ketone group, the complexity might well have been due to the influence of these two groups. Because it contained the ketone group only, P-cholestanone was allowed to react with iodine monobromide. It was surprising to find that it consumed halogen more rapidly (Curves 2, Fig. 1) than did cholestenone. (Of course, it has long been known that it did react with hal~gen.~,')Examination of the curves showed that, while the reaction of cholestanone lacked the aforementioned complexity, it did possess an autocatalytic nature. Dore@ has remarked on the initial lag followed by a rapid consumption of halogen accompanied by a marked evolution of halogen acid when cholestanone reacted with bromine. The above author suggested that substitution had occurred. In the work reported here, the ratios between the total halogen 0 2 4 6 7 consumed and the halogen organically bound were 13 14 two to one, which fact is indicative of substitution. Hours. Fig. 1.-The reaction of iodine monobromide with But P-cholestanol, from which 0-cholestanone is cholestenone, cholestanone, and their oximes: 1, derived, did not undergo substitution under simicholestenone; 2, cholestanone; -e-, oximes; 0 , lar conditions.' Furthermore, substitution, in total halogen consumed; 0, organic halogen. the common sense, would not be expected to display signs of autocatalysis. But a substitution in organic solvents. Third: the initial speed of preceded by an enolization or activation of a ke- the reaction of cholestanone with iodine monotone group could do so. I t is generally conceded bromide was increased when hydrogen bromide that enolization or activation of a saturated ke- was added to the halogenating agent. These tone precedes its bromination. results were similar to those obtained in a like The specific evidence that P-cholestanone also study of cholestenone (Figs. 2 and 3). On the undergoes enolization or activation in its reaction basis of the work of Lapworth,'O Meyer,s Dawwith iodine monobromide is the following. First : son,ll Cohen? Hanson and Williams,12 and of when cholestanoxime was allowed to react with KrOhnke,l3 it is generally conceded that mineral iodine monobromide, no appreciable reaction acids catalyze the enolization or activation which occurred (broken Curve 2, Fig. 1). Of course, precedes the bromination of ketones. Further, this is not absolute evidence that the bromination it is evident that such workers as Butenandt and of cholestanone is via enolization, because the WOW and Ruzicka, et a1.,14.tacitly assume that presence of the oximino group in cholestanoxime cholestanone enolizes during its bromination. might have changed the activity of nearby hydro- Fourth : photographic records of the ultraviolet gen. Second: determinations of the order of the absorption spectra of cholestanone in chloroform, reaction of cholestanone with iodine monobromide in chloroform-glacial acetic acid, and in chlorodisclosed that it was monomolecular. (Table I form-glacial acetic acid-hydrogen bromide (Plate is presented as an example of the results-other 1) and of the enol ethyl ether of cholestanone initial concentrations were also used.) This (Plate 2 ) in chloroform were made. That of finding paralleled those of Meyer,s who studied the cholestanone in the presence of hydrogen the order of the bromination of malonic acid, and (10) Lapworth, J . Chem. SOC.,86, 30 (1904). (11) Dawson. ibid., 96, 1860 (1909); 101, 1503 (1912); ,105, 532 of C ~ h e nwho , ~ studied the bromination of acetone (1914). (6) Dore6, J . Chcm. SOL, 95, 648 (1909). (7) Butenandt and Wolff, B e y , 68, 2091-2094 (1933) (8) Meyer, A n n , 880, 212 (1911). Ber , 44, 218 (1911) (9) Cohm, THISJOUHNAI , 52, 2827-2835 (1930)
(12) Hanson and Williams, ibid., 1059-63 (1930). (13) Krohnke, Bey., 69B,921-935 (1936). (14) L Ruzicka, Bosshard, Fischer and Wirz, Hclu. Chim. Acta, 19, 1147 (1936).
Vol. GO
2
I
/
1.0
3.6
!.4
3.0
2 t .S
L'
1
I1
,.I
,r>
I;
2.4
1.8
7
B
bromide was similar to t.hat of the em1 ethyl ether in chlorofornm. THEORDEKOF
pr.BlnI.n r RRACITON 01'CHOLESTANONE WITITIBr
(.'bolestanone in C V h , I Rr i i i C H C O O I T c 0082 mdl C == 0 041 nihl h l i l l i t g u i v a l r n t ~ Iiqitis hlillirquivnlents Liqitiv. Reaction per time, Con. Conper molr Residual sumed mole UtlII. Ke~idiilrl burned Blaiik (I.lfi4S 0.0000 0.000 0.0824 0.0000 0.000 ,1408 .0410 ,0704 ,0120 .300 2 ,300 .1"3 4 ,040,: ,493 ,0200 :4X8 .otic4 Ordrr is npparently nionomoiwiilar, since t t / t i = I = 2' r- ? a
Reaction time, min.
Blank 2 4
(:liolestunonc i i i CCL, IBr i n CCI; C := 0 0iG4 m M C = 0 035% 1n.M hIillieqtii\deii+s Equiv. Miliieqnivalent.s pEI CoilCoilResidttal sumecl mole Residual sumed 0 1628
1437
0 000 093
0 0704 0 1)OOI)
5tl4 id'!
8 1t i
Order
0 OOO(1 1)Kl
19
.053(i 0480 044'J
0228 0284 0321
Equio, per niole 0 000
ZY7 743 9463
appaiently monomdeculnr
An error of 0 010 cc 111 titration produce.; a mniimurn crror of 0 010 in equivalents per inole when C = 0 TISO m M , and one of 0 020 whr ti C 0 040 in 31
While our experiments were being carried on, Iiihoffen16 reported that cholesterione enolizes during its brornination and that hydrogen bromide stimulates the enolization. We, also, had noted that hydrogen bromide catalyzed the reaction of cholcstenone with iodine monobroniitle L
IT1 Iiihofirn
&I
I
1
T h e in hours. Fig. 2.---The iufluelic-r. of aqueotts hydrogen brumide upon tliri cotisirmptioii o f lialogeti 1)y v h o h t e i i o i i c , Initial hycli ogen lxoinidr conceiitrations 1 n p (i 1, 0,000; 2, (l.020, 3, ~1.042; 4, 0.059; 5, (!.X9; f;, I 1.099,
, 69B,2141-7 (1930)
Ii
1
2 3
1-
/
1
I
5
ii
7
Time in hours. Fig. 3 -The influence of anhydrous hydrogen bromide upon the consumption of halogen by cholestcnonr. Initial hydrogen bromide concentrations, mp 111(j cc : 1, U 000, 2, 0 020, 3, 0 042, 4, 0.059; 5, 0.079; 6,0 099
(Figs. 2 and 3). Further, the reaction of choleswith iodine monobromide in carbon tetrachloride glacial acetic acid, and in carbon tetrachloride alone, was found to be monomolecular. 'I'hese results are similar to those obtained using cholestanone. Cholestenone reacted similarly to cholestanone in one other respect. Cholestenoxime, like cholestanoxime, resisted halogenation iii the preseiice of glacial acetic acid (Fig. 1 and 'l'able TI). (Added hydrogen bromide did not
1enone
TABLE I1 EQUIVALENTS OF HALOGEN CONSUMEDPER MOLE OF SI-HWANCE REACTING WITH IODINE MONOBROMIDB FOR NINEI Y MINUTES In CClr 4- CHaCOOH Iu CClr Substance
111
dir
l a Ht
In air
I n H-
Cholestanone 2 37 2 49 3.49 4 10 Cholestanoxirne 0 11 0 . 13 0 57 0 63 C holestenone 43 .45 0.60 0 80 Cholestenoxime 1-I. .I3 1 17 1 24 Cholestenoxime" .. . ,. 0 80 ... Cholestcnoximeb ,. , .." 1.20 Benzalacetophenone . . . . 1 70 ... syn-Styrylphenylketoxime ,, . 1.42 142 3,S-Diphenylisoxazol ... 1.35 1 37 :
