COMMUNICATIONS TO THE EDITOR
Mar. 5, 1954
1455
for which the Nernst equation a t 2.5’ is E = EO + 0.0296 log ( 0 3 ) / ( H ~ 0 2 -0.0592 ) $” ( 2 ) Supposing that the absolute rate theory as recently applied to polarographic phenomena4 is applicable here, i t can be shown that these equations apply a t the crossing point, however irreversible the waves may be. In fact, Equation (2) was found to hold very well DEPARTMEST O F CHEMISTRY both with regard to the pH and the 02-H202 ratio SORTHTVESTERN USIVERSITY FREDBASOLO {corrected for the acid dissociation of Hz02) over EVANSTOS, ILLIXOIS FRASKP. DWYER the entire range investigated. The value Eo = RECEIVED JANUARY 13, 1954 +O.i’O v. i 0.01 v. was found for the standard potential of the half-cell of Equation (l),in good THE OXYGEN-HYDROGEN PEROXIDE COUPLE AT agreement with Latimer’s calculated value +0.682 THE DROPPING MERCURY ELECTRODE v.5 Sir : These experimental results are also in good The first oxygen wave of the dropping mercury accord with the observations of Berl,6 who found electrode (D.M.E.) arises from the two electron that the 02-H202 couple was reversible a t graphite reduction of oxygen t o hydrogen peroxide. Al- and activated carbon electrodes in solutions of PH though this wave has universally been considered between 13 and 1.5, with an Eoof +0.684 v. highly irreversible, it was recently reported2 that In the range of pH studied the Oz-HzOz couple in unbuffered basic solutions hydrogen peroxide a t the D.M.E. evidently is of the transition (semiyields an anodic wave a t the same potential. reversible) type.’ The situation is complicated From this and other observations the investiga- by the probable presence of two steps8 which may tors concluded that the oxygen-hydrogen peroxide differ in degree of reversibility and dependence on reaction is completely reversible, but involves only pH. Analysis of the irreversible nature of the one electron. waves is continuing with the hope of elucidating These conclusions are not consonant with the the mechanism and kinetics of oxygen reduction. fact that HzOZ (or HOz-) and 0 2 must be the The combined results will be presented in a future diffusing species, and hence two electrons be in- publication. volved in the over-all electrode process; and they (4) Tanford and Wawzonek, “Annual Reviews of Physical Chemisconflict with the insensitivity of the oxygen half- try,” 3, 247 (1952). ( 5 ) W. M. Latimer, “Oxidation Potentials,” 2nd edition, Prenticewave potential (Ell2)to changes in PH, as reported Inc., New York, N. Y., p. 43. by Kolthoff and itliller.a In view of the funda- Hall, (6) W. G. Bed, J . Elecrvochcm. SOC.,83, 253 (1943). mental importance of the oxygen wave in polarog(7) P. Delahay, THISJOURNAL, 75, 1430 (1953); >I. Smutek, Coll. raphy, i t was considered important to resolve this Czech. Chem. Comm., 18, 171 (1953). (8) One of these may he the reversible one-electron step postulated problem, and a preliminary report is provided in by Hacobian, see ref. 2. this Communication. CHEMICAL LABORATORY Polarograms of oxygen, hydrogen peroxide and MALLINCKRODT UNIVERSITY DAVID M. H. KERN their mixtures were run in buffered solutions, pH HARVARD CAMBRIDGE 38, MASS. range 7.5-13, of ionic strength 0.15. In all these RECEIVED JANUARY 27, 19A4 solutions, anodic and cathodic waves were observed, which in the less basic media exhibited the usual criteria of irreversibility-drawn-out shapes, 9a-FLUOR0 DERIVATIVES OF CORTISONE AND HYDROCORTISONE non-linear “log plots,” and in the case of the oxygen wave an El/, which hardly varied with PH. In Sir : I n a recent communication’ we have described mixtures of hydrogen peroxide and oxygen the two waves joined without inflection; however, the E l / , a new group of derivatives of cortisone and hydroshifted as the composition of the mixture was cortisone, in which the %-hydrogen atom is revaried. This irreversible nature diminished as placed by halogen. The main interest in this sethe alkalinity increased, until a t pH 12 both anodic ries of compounds derived from the fact that they and cathodic waves gave identical EI/,’s, and the possessed marked glucocorticoid activity, which in log plot of both had the theoretical slope for a the case of the chloro derivatives exceeded by a factor of 4 that of the parent hormones. The findtwo-electron reaction. At the point a t which the electrolysis current ing that the activity was inversely proportional to in a Hz02-02 mixture crosses the residual current, the size of the halogen atom prompted the preparathe D.M.E. is functioning as a potentiometric tion of the last remaining members of this group, null point detector. The “crossing point” poten- the Sa-fluoro derivatives, the description of which is tial will depend upon the bulk concentration as the purpose of this communication. 9a-Fluorohydrocortisone acetate (I), m.p. 233predicted by the Nernst equation, provided that we are dealing with the over-all reaction 23402; [ c Y ] ~$123’ ~ D ( 6 , 0.64 in CHCI,); ,;:A: 238 m p ( E = 16,800); A”,?’ 2.94 p , 3.03 p (OH), 5.75 0 2 2H+ + 2e- _r H202 (1) p , 5.82 p (acetylated side chain), 6.07 p , 6.11 p (1) Kolthoff and Lingane, “Polarography,” 2nd edition, Vol. 11, perimental support to the postulate of orbital stab i l i ~ a t i o n . ~The susceptibility of the mono compound, 1.8 B.M., corresponds to one unpaired electron. This is not consistent with the theoretical values expected from the simple formula [FedipyClz] and may suggest a certain amount of metalmetal interaction. Detailed studies on these and similar compounds will be published later.
+
Interscience Publishers, Inc., New York, N.Y., p. 652. (2) S. Hacobian. Ausfralian Journal of Chemistry, 6 , 211 (1863). (3) I. M. Kolthoff and C. 5. Miller, THISJOURNAL, 68, 1018 (1941).
(1) J. Fried and E.F. Saho, THISJOURNAL, 76, 2273 (1963). (2) Occasionally samples began t o melt at 205-208’, reiolidiEed and eventually melted at 228-228O, probably due to polymorphiam.
COMMUNICATIONS TO THE EDITOR
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L-01. 76
(A4-3-ketone); (Anal. Calcd. for C23H3106F : C, Amax. N'jol 3.06 p (OH), 5.72 p, 5.81 p (acetylated side 65.39; H, 7.39; F, 4.52. Found: C, 65.32; H, chain), 6.11 p (A4-3-ketone); (Anal. Calcd. for 7.26; F, 4.50) was obtained in about 50% yield C Z ~ H ~ Z OC,~ S59.98; : H, 6.71; S, G.G7. Found: when A4-pregnen-9~,11~-oxido-21-ol-3,20-dione 21- C, 60.01; H, 6.73; S, 6.35). Additional data are acetate' (11) was treated with anhydrous hydrogen required to permit a satisfactory structural assignfluoride in alcohol-free chloroform a t 0"for 4.5 hours. ment for 1V.j I possessed 10.7 f 2.3 times the activity of corti(5) Although the above data are not sufficient to establish t h e sone acetate in the rat liver glycogen assay3which is structure of IV, certain structural possibilities can be ruled out on the in keeping with the relationship between activity basis of the available evidence. Thus, the reactivity of the new hyand size of the halogen atom established for the droxyl group toward acylating agents appears to exclude the presence an Ilp-hydroxyl in a conventional ring C-saturated steroid. The other halogenated derivatives. Deacetylation of I of structure, which for steric reasons might be expected allylic A~"-llp-ol with sodium methylate afforded Sa-fluorohydro- to be susceptible to acylation (or any other allylic structure) is concortisone, m.p. 260-262' (dec.) ; [ ( Y ] ' ~ D +139" sidered unlikely, since (1) IV is resistant t o oxidation witn manganese (c, 0.55 in 95% alcohol); 239 mp ( E = 17,- dioxide (cf. F. Sondheimer, C. Amendolla and G. Rosenkranz. THIS JOURNAL, 76, 5930 (1953)). and (2) the changes in molecular rotation 600); ?'A:: 3.01 p (OH), 5.54 p (20-carbonyl), 6.07 attending propionylation (+ZOO) and mesylation ( + 4 9 O ) of IV are considerably smaller than those produced by acylation of allylic alco1.1, 6.20 p (A4-3-ketone); (Anal. Calcd. for Czlhols (d. W. Klyne, H e i v . Chinz. Acta, 35, 1224 (1952)). Rotational H2905F: C, 66.30; H, 7.68. Found: C, 66.49; data likewise serve to exclude the a pviori less likely AT-115-01 strucH, 5.22). Oxidation of I with chromic acid ture, inasmuch as the average contribution of the 7,8-double bond in yielded Sa-fluorocortisone acetate (111), m.p. 254- two AM-3-ketones is -304' (cf. R. Antonucci, S . Bernstein, R. Lenhard, K. J. Sax and 1. H. Williams, J . Org. Chem.. 17, 1369 (1952)) as 25.5'; [ f f I z 3 D +155' (c, 0.45 in CHC13); A$:x. compared t o a value of +516' for the difference between IV and hydro234 mp ( E = 17,000); AZig' 2.86 p (OH), 5.72 p, cortisone acetate. Among the more likely possibilities being con5.78 p , 5.83 p (11-ketone and acetylated side chain), sidered a t the moment are structures arising from I1 by a WagnerMeerwein type rearrangement involving CP. 6.05 (A4-3-ketone); (Anal. Calcd. for Cd&&6F: INSTITUTE C, 65.70; H, 6.95. Found: C, 65.62; H, 7.19), THESQUIBB MEDICAL RESEARCH JOSEF FRIED which on deacetylation furnished the parent al- FOR NEWBRUNSWICK, NEWJERSEY EMILY I?. SARO cohol, m.p. 261-262'; [ a I z 3+144' ~ (c, 0.41 in RECEIVED FEBRUARY 3, 1954 CHCI3); A$:;. 234 mp ( E = 16,000); ?'A;: 2.88 p (OH), 5.87 p (11- and 20-keto groups), 6.08 p (A4-3-ketone); (Anal. Calcd. for CZIHZ~OF,F:C, THE STIMULATION OF SERINE BIOSYNTHESIS IN BY TETRAHYDROFOLIC 66.65; H, 7.19. Found: C, 66.50; H, 6.98). PIGEON LIVER EXTRACTS ACID I11 had 9.0 2.7 times the activity of cortisone Sir: a~etate.~ Serine biosynthesis has been postulated to occur The reaction of I1 with hydrogen fluoride afforded in addition t o I an isomer of I1 (1070 yield) (IV), by a process resembling the Mannich reactionzs3: m.p. 259-262'; [a]z3~ +272O (c, 0.53 in 9570 the a-carbon of glycine, activated by Schiff base formation between glycine and pyridoxal phosalcohol) ; 239 mp ( E = 20,200) ; ?'A:: 2.93 p , phate, combines with a condensation product of 3.03 p (OH), 5.75 p, 5.82 p (acetylated side chain), formaldehyde and tetrahydrofolic acid (THFA), N56.12 p, 6.16 p (A4-3-ketone); (Anal. Calcd. for hydroxymethyltetrahydrofolicacid. Serine is proC23H3006: C, 68.63; H, 7.51. Found: C, 68.60; duced by hydrolytic cleavage of the resulting prodH, 7.40)) in which the epoxide group has been re- uct. arranged to form a double bond and a readily acylStudies have been reported indicating that able hydroxyl group. Thus, I V on titration with pyridoxal phosphate participates in serine bioperphthalic acid consumed one mole of peracid with ~ y n t h e s i s . ~In . ~ the present communication, exthe formation of an epoxide, m.p. 213-214' (dec.) ; perimental evidence supporting a cofactor role of [ a I z 3 D +237" (c, 0.59 in CHC13); ,x:A: 237 mp THFA in this reaction is described. ( E = 16,100); $':A: 2.92 p, 3.06 p (OH), 5.73 p , Pigeon liver extracts prepared as described by 5.80 p (acetylated side chain), 6.16 p (A4-3-ketone); Berg6interconvert glycine and serine (Anal. Calcd. for C23H3007: C? 66.01; H, 7.23. CHzOHCHNHzCOOH "Ci" CHzKHzCOOH Found: 66.03; H, 7.44), on treatment with propionic anhydride and pyridine a t room temperature Formate and formaldehyde are utilized for the afforded a propionate, m.p. 261-26404; [ a I z 3 D formation of the "C1" unit. These properties are +260° (c, 0.40 in CHC13), +243O ( 6 , 0.52 in 95% lost on treatment of the liver extracts with Dowex-1 alcohol); AzC,.,, 238 mp ( E = 18,300); Xz:c' 3.03 (chloride). The ability of inactivated6 pigeon liver extracts p (OH), 5.72 p, 5.80 p (propionyl and acetylated to interconvert serine and glycine has now been side chain), 6.07 p, 6.11 p (A4-3-ketone); (A~zal. (1) This investigation has been supported b y a grant-in-aid from Calcd. for Cz~H340,: C, 68.10; H, 7.41. Found: American Cancer Society upon recommendation of the Committee C, 67.93; H, 7.36) and with mesyl chloride in the on Growth of the National Research Council. pyridine a t 0" formed a mesylate, m.p. 151-152' (2) W. Sakami, American Chemical Society Symposium on 1Carbon Compounds, Chicago, September, 1953. (dec.); [ a l Z 3+260° ~ (c, 0.54 in CHC13), +238" In the Mannich reaction formaldehyde couples either ammonia, (c, 0.35 in 95% alcohol); 237 mp ( E = 17,800); or (3) a primary or second'ary amine with an atom possessing an active
*
Xzx,
+
(3) M. L. Pabst, R. Sheppard and M. H. Kuizenga, Endocrinology, 41, 55 (1947). We are indebted t o Drs. A. Borman and F. M. Singer for the liver glycogen assay data. A detailed account of these and other assay results will be published elsewhere. (4) A mixture of I V and its propionate melted a t 236-252°.
hydrogen. (4) S. Deodhar and W. Sakami, Fedevalion Proc., 12, 195 (1983). (5) P. Berg, J. Biol. Ckem., 205, 145 (1953). (6) Extracts treated with Dowex-1 (chloride) and dialyzed for 15-16 hr. against flowing 0.1 M K-phosphate buffer, p H 7.5.
