in benzene solution was achieved only with the coupling constants of opposite signs. The spacings between the lines shown in Fig. 1 at 241.7 and 243.7 cps. and 221.9 and 220.7 cps. (Fig. 1) were reduced to 1.4 and 0.1 cps., respectively, a t 40 Mc, IVith coupling constants of the same sign, the computed spacings for these lines were 0.S and 0.9 cps., respectively. On the basis of these results, we believe that the relative signs of JAC and J B C must be taken as being indeed different from JAB. Interestingly, this conclusion could only have been reached by treatment of the spin system as 9BC3, not as the ABX3 approximation in which a change in the sign of J A B relative to J.kc and J ~ does c not affect the theoretical spectrum. The results can be regarded as disquieting in two connections. First, the difference in sign between the geminal and vicinal H-H couplings runs couiiter to the theoretical predictions of Karplus arid Gutowskylo for substances with normal bond angles. Second, in analogy with the findings of Castellano and Ji'aughll for ABC systems, rather different sets of spin-coupling and chemical-shift parameters were found to give nearly identical theoretical spectra for diethyl sulfite in benzene and each of these corresponds amazingly well to the experimental spectrum a t GO 11c. Indeed, the previously mentioned excellent agreement between theoretical and experimental spectra obtained for acetaldehyde diethyl acetal now has been duplicated with V B - v.4 = 9.23 cps., vc - V A = 146.3 cps., J l ~ c= 9.30 cps. and J A Ceqiinl to J B C = 7.03 cps. with J A Bopposite in sign to JAC and J B C . Clearly, caution and judgment must be exercised in use of the iterative method of obtaining spinspin coupling constants since there seems to be no assurance that a "final" solution is truly Acknowledgment.-11-e are deeply indebted to Dr. Stanley L. Manatt and the Computing Center of the Jet Propulsion Laboratory for the I B I I 7090 calculations of the theoretical spectra. (IO) €1. S. Gutowsky, M . Karplus and D. hI. Grant, J. Chcnz. P h y r . , 31, 1278 (lL69); hI.Karplus, ibid., 30, 11 (19.59) (11) S. Castellano a n d J. S. Waugh, ibid., 34, 295 (1961).
-3 ,& --C":,
& J -
H0
(-,
'143
lI>IL.S
\
110
I
11, R'=H III? K ' = C H 3
progesterone by Oppenauer oxidation. Only about 20% of the "normal" product, the corresponding I 7a,20-dimethyl-5-pregnene-3P,20-diol, carbinol was formed and conveniently separated by chromatography. Analogously, the 3a,Cia epoxide obtained by peracetic acid treatment of I, m.p. 1TO-1'71", [ a ] D - 67.2, gave in similar yields 3fl,3a-dihydroxy-G@,lia-dimethylpregnan-2O-one, m.p. lSS-192",which was directly oxidized by chromic acid to the 3,20dione, n1.p. 230-233", and converted by niethanolic sodium hydroxide to 6 a ,17-dimethylprogesterone, ~ Am,, 239 mp, log E 4.2. 1n.p. 137-140°, [ a ]+90.3, The latter substance, and the corresponding B-dehydro derivative, m.p. 143-14(j0, [ @ I D +87.1, Amax 292 mp, log e 4.4, obtained by chloranil dehydrogenation, were orally a t least as active, in the Clauand berg test, as 19-nor-lia-ethynyltestosterone, twenty times more active than 170-methylprogesterone. KOTEADDEDIS P~uo~.-ij,l7-Dimethy~-6-dehJ.droprogesterone is as active orally as Ba-rneth~-l-17-acetoxyprogesterone. It is devoid of any androgenic properties.
Treatment of I with ethylmagnesium iodide in anisole gave lTa,21-dimethylpregnenolone 111, m.p. 145-14So,with no detectable amount of carbinol being formed. Oppenauer oxidation gave 1ia,21-dimethylprogesterone,m.p. 1S7-l~59°, [ a ] D +1Oi.i, A,, 2-1-1 m p , log E 4.2' in 705; over-all yield. Further transformations of these methylated steroids together with a report on their G-halogenated derivatives3will be presented in a more detailed paper. .ail new compounds ( 2 ) All rotations in 1'; chloroiurm solution had satisfactory elemental analysis We are indebted t o l)r. G. Papineau-Couture and his associates for the analytical data and t o Drs C . Chappel and C.Kevesz for the bioassays. f ~ 3 )Prepared by Dr. Y. Lefebvre of these laboratories
CONTRIBUTION KO.2738 FREDKAPLAN GATESAND CRELLIN LABORATORIES OF CHEMISTRY .\"ERST RESEARCH LABORATORIES CALIFORNIA INSTITUTE O F TECHNOLOGY l i . I)EGHESGHI PASADESA, CALIFORNIA JOHX L). ROBERTS I). 0. Box 6115 R . GAUDRY MONTREAL, P. Q., CANADA RECEIVED AUGCST9, 1961 RECEIVED SEPTEMBER 20, 1961 STERICALLY CONTROLLED GRIGNARD REACTIONS. A NEW SIMPLE ROUTE TO METHYLATED STEROID ANALOGS
17a-
Say:
INERTIAL EFFECTS OF SUBSTITUENTS ON HOT ATOM CAPTURE'
Sir:
We wish to report a convenient new synthesis of Hot hydrogen atoms can replace hydrogen and 17a-methylated steroid derivatives which has made other atoms and groups with high collision effipossible the preparation of highly active proges- ciency.2 The course of these reactions has been terone homologs When the readily available shown to be largely controlled by steric factors.' (I) was However certain results, particularly on alkyl remethyl 3~-hydroxy-l7a-methyl-5-etienate refluxed in anisole for one hour in presence of placement, have not found explanation. This excess niethyhagnesium bromide, the correspond- letter reports a remarkable new effect in the hot ing sterically hindered ketone, 17a-methylpregnenol- hydrogen displacement of halogen atoms from one 11' was obtained in 70yoyield. The latter sub(1) Studies supported by the U. S . Atomic Energy Commissivll. stance was converted to the known' 17a-methyl- Contribution S o . lBS1 from the Sterling Chemistry Laboratory. ( 1 ) PI. 4 Plattner, H H r u s v r P Th H e r z i g , 32, 270 ( l Y l %
Hell
Chrin A r l o
(2) D. Urch and K. Tb-olfgang.,J . A m . Chem Soc., 83, 2982 (1961). This paper contains references t o t h e earlier literature
CORIMUNICATIONS TO THE EDITOR
Nov. 20, 1961
halomethanes. Its interpretation involves recognition of factors that appear to control hot atom substitution of heavy atoms and groups. High kinetic energy (hot) hydrogen in the form of tritium recoiling from the He3(n,p)T nuclear process was allowed to react with the various fluoro-, chloro- and bromomethanes. The techniques of carrying out such reaction, the suppression of competing thermal processes and the analysis of the tritium-containing products have been described previously. The most significant results on the fluoro-methane series are summarized in the table. While replacement of F by T is quite probable in CH3F, it is much less so in CH2F2, and almost non-existent in CHF3 and in CFd. By contrast replacement of H by T changes much less within this series. Exactly parallel trends appear in the chloro- and bromomethanes.
4669
DISPLACE MEN T WITH CAPTURE
CH3F DISPLACEMENT WITH CAPTURE
L 2 L2 I
C
CHZb )ISPLACEMENT USJALLY WITHOJT CAPTURE
9 I
Y
Fig. 1.-Effect of substituent mass on orbital availability TABLE I for hot atom capture: results of hot hydrogen attack on SINGLEATOM DISPLACEMEST BY HOT TRITIUMIN FLUOROsubstituted methanes. The length of the arrows represents METHASES relative velocity-. Possible capture by the fluorine atom is ReactDisplacement of H Displacement of F ing Pield/ Yield/ not indicated. fluorocarbon
Yield,
Product
%*
C-H
bond
CH4 CHBT 28.0 7 . 0 CH3F CHzFT 12.7 4 . 2 CHZF? CHFzT 5.8 2.9 CHFs CF3T 2.9 2.9 CFa ..... .. .. Relative t o total T reacting.
Yield,
C-F
Product
%*
bond
. ... .
..
..
CHPT CHzFT CHFtT CFaT
5.3 1.6 0.7 0.3
5.3 0.8 0.2 0.1
This phenomenon may be understood by considering the reactive collision in detail. Hot hydrogen displacement of a hydrogen atom has been discussed previously : The impinging hot atom approaches in a direction approximately normal to the C-H bond and, on collision, ejects the bound hydrogen with a velocity comparable to that of its own approach. I t can thus occupy the same position held by the ejected atom and be bound by the existing orbital (see Fig. 1, XI-AIIII). Variations in probability of C-H bond displacement (as in Table I) can be accounted for on the basis of steric hindrance to approach by neighboring atoms or groups. A model of hot hydrogen displacement of a fluorine atom cannot be as simple. The hot atom approaching the C-F bond a t an approximately normal angle can on collision break it, largely by displacing the binding electrons, thus greatly weakening the bond, and also by imparting a major fraction of its momentum to the fluorine. However, the comparatively large inertial mass of the fluorine causes it to move out only slowly, thus preventing the incident hydrogen from immediately occupying its position in space (see Fig. 1, BI-BII). As a result, the hot hydrogen will be far off the tetrahedral angle for sp3binding and is only very weakly bound to the carbon. It would therefore tend to recoil from this position of high potential energy and be captured by the fluorine or escape as a free atom. The C-T bond can, however, be strengthened and the tritium retained as the whole molecule turns, thus reestablishing tetrahedral binding.3 Such (3) Contrary t o a possible intuitive impression, significant rotation of t h e CHs “away” from t h e tritium is not induced by t h e collision
rotation must be completed in the order of sec.-the time required for a 1 e.v. T atom to move 1 A. The corresponding rotational energy of a CH3 group is a few e.v.-an energy that becomes available by forming a strong C-T bond. Actually this rotation also can be described as a restoring bending motion of the CH3 relative to the T. A coupling mechanism for inducing rapid rotation therefore exists and the T atom can be captured on fluorine displacement in CH3F (see Fig. I, BIII).4 This is confirmed by the data. By contrast if the residual group has heavy substituents in addition to that being displaced its much greater moment of inertia will preclude rapid rotation to strengthen the C-T bond (see Fig. 1, CI-CHI). Such rotation would require of the order of tens of e.v. and there is no efficient mechanism of providing this much energy. As a result attack on a C-F bond in CH2F2,CHF, and CF4 is unlikely to result in capture of the hot atom by the fluoromethyl group. The low efficiency of halogen displacement in all polysubstituted methanes thus follows naturally. The model formulated provides an explanation of the earlier and unexplained observation* that recoil tritium attack on a C-C bond invariably results in the favored capture of the hot hydrogen by the simpler radical. Thus neopentane yields eight times as much CH3Tas (CH3)&T.* On rupture of the C-C bond the smaller group can rotate more rapidly to establish a strong bond and is thus favored in the competition for capture of the hot atom. -4 critical experiment was carried out on H3C-CF3 to test this hypothesis as against two itself. If in colliding with t h e C-F bond, a 5 e.v. T atom yields half its momentum to t h e carbon, t h e C a t o m thus acquires approximately 0.3 e.v. Nearly all this energy is translational, less t h a n 0.1 e.v. being in rotation about t h e center of mass of t h e CHI. This is insignificant on t h e time scale of t h e collision and negligible compared t o t h e restoring bendinn force if a C-T bond is formed. (4) T h e tritium atom (Fig. B 1 , 2 ) will also tend t o insert b y directly pushing apart t h e C and F atoms. This vibrational stretching relaxation is too slow t o be very effective; t h e inertial effects are therefore considered t o be primarily, though not purely, rotational.
4670
Vol. 83
CONMUNICATIONS TO THE EDITOR
others.? An explanation based on steric obstruction would predict a ratio CH3T/CF3T smaller than that of C H I T / C ( C H ~ ) ~from T neopentane; and one based on bond strength would predict that CH3T/ CF3T be unity since the strengths of the CH3-T and CFa-T bonds are virtually equal. The experiments showed a ratio CH3T/CF3T in excess of twenty, confirming the present model. Competition for capture of the hot atom is thus controlled by the same factor in attack on both C-C and C-X bonds: The availability of a strong bonding orbital within the time of collision, where this is governed by the inertia of the substituents on the central atorrts. This principle should be completely general for hot atom reactions but has no counterpart in therinal processes.
(shoulder). Reaction of IIa with ketene occurs exothermically to give 24% of heptafluorocyclobutyl acetate (IIIa), b.p. 99-101'. Anal. Found: C, 30.1; H, 1.4; F, 55.2.
(1) (a) D. C England, J . Anz. Chem. Soc., 83, 2205 (1961). (b) S. Andreades and D. C. England, Abstracts, 140th Meeting of t h e Amrrirau Chemical Society, September, 1961. p. 14-M.
(9) GY. Olah and A . Pavlath, Acta. Chim. Acad. Sci., Hungary, 3, *03 (1953), a reduction i n ether
-!-
IIa-IId
CH,=C=O
--+
OCCHB
IIIa, X = F, IIIc, X = Br IIIb, X = C1, IIId, X = I
In a similar manner, the alcohols 1Ib--IId were prepared by the addition of the appropriate hydrogen halide to I in 73-90% yields and these alcohols were converted to the corresponding acetate IIIbIIId in 3841% yields. Consistent elemental analySTERLING CHEMISTRY LABORATORY ses, infrared, FI9 and H ' n.1n.r. spectra were obYALEUNIVERSITY ROBERT ODUM tained for all of the products describedS2 N E W HAVEN, CONNECTICUT RICHARD WOLFGANG In the absence of moisture, all of the alcohols were RECEIVED SEPTEMBER 16, 1961 reasonably stable on storage except IId which slowly liberated iodine. At elevated temperatures, the equilibrium becomes unfavorable and the alcoa-HALO ALCOHOLS hols revert to some extent to ketone and hydsogen Sir : Mre wish to report the first preparation and isola- halide. This is a particular problem with I I a in tion of certain a-haloalcohols in pure form, and to glass apparatus since prolonged heating will condescribe some studies of hydrogen bonding in sume H F (shifting the equilibrium to the left) and these systems. Hexafluorocyclobutanone (I), an reaction of H F with glass produces water which also attacks the alcohol. Ketones and hydrogen halides ordinarily do not give stable addition Compounds.3 f 4 Vorlander obtained some unstable ketone-hydrogen halide complexes3 but the presence or absence of alcohol or ketone functions in these materials was not esI I1 tablished. In general, 1,l-halohydrins cannot be IIa, X = F isolated in pure form because of the rapid establishIIb, X=C1 IIc, X = B r ment of the addition-elimination IId, X = I For example, 2-chloro-2-~propanolcannot be isoIIe. X = O H lated from an acetone-HC1 mixtureGalthough 1: 1 F and 1: 2 acetone :RF nondescript complexes were IIf, % o b ; reported in 1SS3.6 F2 Previous attempts to prepare perfluorinated afluoroalcohols have been unsuccessfu1,7~8although extraordinarily reactive ketone,'" reacts rapidly at one example of an a-fluoroalcohol, monofluorolow temperatures with hydrogen halidesIb to give methanol, has been ~ e p o r t e d . ~ the distillable a-haloalcohols IIa-JId in high yields. Neither ring strain factors nos fluorine substituThus, equimolar quantities of I and hydrogen tion adjacent to the carbonyl function, alone, can fluoride were condensed in an evacuated Monel account for the stability of these a-haloalcohols vessel at -195". After allowing the mixture to relative to the ketones since neither a-fluorocyclowarm to +20°, distillation in a nitrogen atmos(2) Difficulties were encountered in obtaining good analytical values phere through a thoroughly dry glass column gave a I I I d . These data will appear in a future publicatiun. 75% yield of heptafluorocyclobutanol (IIa), b.p. f o r(3) D. VorlLnder, Atin., 341, 15 (1905). 57-58' (some dec.); b.p. 6" (85 mm.); Found: C, (4) W. Hhc!
