790
Vol. 78
D. J. CRAM,F. D. GREENEAND C. H. DEPUY
second recrystallization from the same solvent raised the m.p. to 168-169'; AmX a t p H of 1,254 mp. A n d . Calcd. for QH8NaO: C, 51.2; H, 4.9. Found: C, 50.9; H , 4.9. Preparation of 6-Methylmercaptopyrazolo(3,4-d)pyrimidine (IV).-To 150 ml. of ethanol was added 10 ml. of concentrated ammonium hydroxide, 7.0 g. of 4-chloro-6-methylmercaptopyrazolo(3,4-d)pyrimidine (VIII) and 2.7 g. of 10% palladium-on-carbon. The solution was shaken on the low pressure hydrogenator a t a hydrogen pressure of 20 lb./ sq. in. for 24 hours, after which time the uptake of hydrogen had ceased. The solution was filtered and the filtrate evaporated to dryness on the steam-bath. The residue was recrystallized from an 80% ethanol-water mixture to yield 1.7 g. of white crystals, m.p. 201-204'. A second recrystallization from the same solvent raised the m.p. to 210212'; Amax a t pH of 1, 240 and 300 mp. Anal. Calcd. for CaHcNS: C, 43.4; H , 3.6; N, 33.7. Found: C, 43.0; H , 3.5; N, 33.1. Preparation of 4-Methoxy-6-methylmercaptopyrazolo(3,4-d)pyrimidine.-To a solution of 1.0 g. of sodium in 75 ml. of absolute methanol was added 4.0 g. of 4-chloro-6methylmercaptopyrazolo(3,4-d)pyrimidine ( V I I I ) . The solution was heated for four hours on the steam-bath and then neutralized with glacial acetic acid. The cooled solution yielded 3.1 g. of white needles, m.p. 190-192'. Recrystallization from a methanol and water mixture raised the m.p. to 193-194'; Amax a t pH of 1, 240 and 282 mp. Anal.
[CONTRIBUTION FROM
THE
Calcd. for C.rHsNdOS: C, 42.9; H , 4.1; N, 28.6. Found: C,43.0; H , 3.9; N, 29.0. Preparation of 4-Substituted-aminopyrazolo(3,4-d)pyrimidines (XVI) (see Table I). General Method 1.-Five to ten grams of 4-chloropyrazolo(3,4-d)pyrimidine(XV) was added to 50 to 100 ml. of a 2 5 4 0 % aqueous solution of the primary or secondary amine. The solution was heated for four hours on the steam-bath and then allowed to cool in the refrigerator overnight. The filtered precipitate was then washed with a little ice-water, dried and recrystallized from the solvent indicated. General Method 2.-Five to ten grams of XV was added to approximately 0.15 mole of primary or secondary amine dissolved in 150 ml. of absolute ethanol. The solution was heated for four hours on the steam-bath a t which time the volume had been reduced to approximately 50 ml. The solution was cooled overnight and filtered. The crude product was then recrystallized from the indicated solvents. Preparation of 4-Substituted-amino-6-methylmercaptopyrazolo(3,4-d)pyrimidines (111) (see Table II).-The preparation of these compounds was carried out by treating 4-chloro-6-methylmercaptopyrazolo(3,4-d)pyrimidine (VIII ) according to general method 1 or general method 2 for the preparation of 4-substituted-aminopyrazolo(3,4-d)pyrimidines (XVI). LASVEGAS,NEW MEXICO
DEPARTMENT O F CHEMISTRY OF
THE
UNIVERSITY
OF
CALIFORNIA AT
LOS
ANGELES]
Studies in Stereochemistry. XXV. Eclipsing Effects in the E, Reaction1 BY DONALD J. CRAM,FREDERICK D. GREENEAND C. H. DEPUY RECEIVED XOVEMBER 23, 1954 Eclipsing effects in the E2 reactions of the diastereomers of the 1,2-diphenyl-1-propyl-X system have been studied as a function of the leaving group [X = C1, Br and +N(CHg)3], of the solvent [CzHbOH, ~ - C ~ H I ~ C H O H C (CH3),COH, H~, nC~HI~OH C ,Z H ~ ( C H ~ ) ~ CCeHB], O H , and of the base [C2H60Na,~ - C ~ H I ~ C H O K (CHg)aCOK, CH~, n-C8H1;ONa, C?H5(CHa)tCOK]. The ratio of rates kEn threo/kE, erythro varied from 1-11 with X = C1, the value of the ratio increasing with increasing base strength and decreasing solvating ability of the medium. With X = Br, the rate ratio varied between 0.7 and 5.4, the solvent and base strength effects being similar to those found when X = C1. With X = +X(CH3)3, the rate ratio was 57 in CzHbOH with C2H60Na as base. In (CH3),COH with (CH,),COK as base, the rate ratio was about 1, but in this case trans-olefin was obtained from both diastereomers. I n all other cases a trans elimination occurred, the threo isomer giving The trans and the erythro isomer giving cis-a-methylstilbene. Equilibration of the olefins with acid gave translcis -50. variation in rate ratios is interpreted in terms of the variation of the transition state from a geometry similar to that of the starting material (no groups eclipsed) to one similar to the product (four groups eclipsed).
Differences in reactivity of diastereomeric compounds have been recognized for about seventy-five years, as has the fact that cis-trans-olefin pairs possess different thermodynamic stability. Eclipsing effects have been invoked only relatively recently to explain these phenomena and have been discussed in connection with both the relative thermodynamic stability of isomeric substances and the relative stability of isomeric transition states arising from either the same compound or diastereomerically related compound^.^ Two distinct problems (1) This work was sponsored b y t h e Office of Ordnance Research,
U.S. Army. (2) For summary articles of t h e earliest literature, see: (a) P. Pfeiffer. 2. physik. Chem., 48, 40 (1904); (b) P. F Frankland, J . Chem. Soc., 654 (1912). (3) With respect t o t h e thermodynamic stability of isomeric olefins see: (a) G. B. Kistiakowsky, J. R. Ruhof?, H. A. Smith and W. E. Vaughan, THISJOURNAL, 57, 876 (1935); (b) R. B. Williams, i b i d , , 6 4 , 1395 (1942); (c) D. J. Cram, i b i d . , 71, 3883 (1949); (d) D. Y. Curtin and B. Luberoff, Abstracts of Thirteenth National Organic Symposium of t h e American Chemical Society, Ann Arbor, Mich., June, 1053, p. 40; (e) R . Y.Mixer, R . F. Heck, S. Winstein and W. G. Young, THISJOURNAL,75, 4094 (1953). Regarding differences in thermodynamic stability of diastereomeric 1,2-dimethylcycluperit anes, see: ( f ) W. Beckett, K. S. Pitzer and R. Spitzer, ibid., 69, 2488 (1947). With respect t o reactivity differences in closing five-ruemi,ererl rings, , 338 (1924). For exaiuiile,; s r e . ( E ) 13. Hermans, Z . p h y s i k . C h c ~ .113,
arise with respect to the magnitude of eclipsing effects in transition states, the first involving the bulk of the groups, and the second concerning the degree to which these groups are actually e ~ l i p s e d . ~ The bimolecular .elimination reaction as applied to diastereomerically related starting materials posof reactivity differences in 1,2-molecular rearrangements, see: (h) D. Y. Curtin, P. I. Pollak, E . E. Harris and E. K. Meislich, THIS JOURXAL, 78, 961 (1930), 73, 992 (1951), and 74, 2901. 5518, 5905 (1952); (i) D. J . Cram and F. A. Abd Elhafei, i b i d . , 76, 28 (1954). Examples of t h e phenomena as applied t o acyl migrations are: (j) L. H. Welsh, ibid , 69, 128 (1947~,and 71, 3500 (1949); (k) ' f f . Bruckner. G. Fodor, J. Kiss and C. Kovacs, J. Chcm. Soc., 885 (19481, and subsequent papers. Reactivity differences as applied t o t h e 1.2elimination reaction are: (I) W. G. Young, D. Pressman and C . D. Coryell, THISJOURNAL,61, 1640 (1939); ref. 3d; (m) R . E. Lutz, D. F. Hinkley and R. H . Jordan, ibid., 73, 4649 (1951): (n) S. Winstein, E. Grunwald, K. C. Schreiber and J. Corse, i b i d . , 74, 1118 (1952), and quoted references; ref. 6 ; (0) D. Y. Curtin and D. B. Kellom, ibid., 75, 6011 (1953); (p) D. J. Cram and J. D. McCarty, i b i d . , 76, 5740 (1954). F o r a n example of eclipsing effects in the reverse aldol condensation, see: (9) H. E. Zimmerman and J . English, Jr., ibid., 76, 2285, 2291. 2294 (1954). For an example of a reactivity difference in t h e formation of a chloronium ion, see: (r) S. Winstein and D. Seymour, ibtd., 68, 121 (1946). (4) D. Y.Curtin. e t d ,(ref. 3 d . 30 and Rectwd Chpm. P u o g r r \ P , 15, 1 I I (19.54)) have introduced t h e term "cis etTect" i n cc,nnecliuii witit their extensive currelatimi < ) [ ditTerences in reactivity (or stability) of iscmers with t h e diRerences in bulk of groups 1,ecoiniul: eclil,setl.
ECLIPSING EFFECTSIN
Feb. 20, 1956
THE
Ez REACTION
791
phenyl group.g Since the groups attached to the >C=C< in the olefins are eclipsed and those * * groups attached to the $C-C< in the diastereomers are not, the differences in stability of the former compounds should be markedly greater than those of the latter. Kinetics of the Elimination Reaction.-Table I records the kinetic data for the reactions of threoand erythro-l,2-diphenyl-l-propyl-X in which X = C1, Br and *N(CH3)3. I n those runs where X = C1 and Br, the reaction rates were followed by titrating the liberated halide ion by the Volhard method. Where X = +N(CH3)3, the reactions were followed spectrophotometrically, making use of the intense absorption in the ultraviolet of the two olefins. Since with the concentrations of base and alkyl halide employed the pseudo first-order and second-order rate constants do not differ within experimental error from one another, only the former are employed, except in runs 26 and 27, conducted in benzene, where the concentration of base and alkyl halide are of the same order of magnitude. I n these two runs, true second-order rate constants are used. In all cases, a minimum of five points are CHI X I 1 -Xtaken, the average being seven. B : + CsHj-C-CH-CsHs -+ The kEI’s (measured as pseudo first-order rate I* * constants) of Table I are corrected by the yields of H CHI olefin obtained in each run (Table I) in those reacI 1 tions followed by the titrimetric method. I n those BH GHr--C=CHCeH5 reactions followed spectrophotometrically, k E 2 was I1 measured directly. Outside of the two runs (26 The effects of four factors on the reaction rates have and 27) made in pure benzene, no drifts in rate been studied: the nature of the leaving group, the constant with time were observed. solvent, the strength of the base, and the size of the I n ethanol with X = C1, a change in base conbase . centration from 1 to 2 N represents a change in meThermodynamic Stability of Products and Start- dium which is not reflected in a variation of k E 2 ’ s ing Materials.-Pure samples of cis- and trans-a- for the diastereomers. I n the other solvents the methylstilbene (11) were prepared,sb equilibrated small amount of data available suggests that over under acid conditions, and each resulting mixture the range of base concentrations employed, the was analyzed, making use of the differences in ul- kEis vary approximately linearly with base contraviolet absorption spectra of the two olefinssa centration, and that the rate of change of k E , (see Experimental). The trans isomer (two phenyl with base concentration is independent of which digroups trans) predominated in the product by a fac- astereomer is involved. tor of a t least 50/1. Unfortunately, means are not Products of the Elimination Reaction.--The available for equilibrating the diastereomeric start- stereospecific character of the base-induced eliminaing materials themselves [I with X = C1, Br and tion reaction of the threo- and erythro-l,2-diphenyl+N(CH3)3]. However, the diastereomeric formates 1-propyl chlorides and bromides with potassium (I with X = OCHO) have been equilibrated in ethylate in ethanol and with potassium 2-octylate in formic acidsc and have been found to be of about benzene was established previously through prodequal energy (threojerythro = 0.82). Since the bulk uct isolation experiments.*b I n the present study of a chlorine or bromine atom does not differ much the olefin produced in all but runs 26 to 29 (benzene from that of a formate group, one might expect present in the solvent) was examined spectrophotothese diastereomeric halides to be of approximately metrically. Since cis-a-methylstilbene possesses the same energy, with possibly the erythro isomer Amax 262 m p ( E 11,700) and trans-a-niethylstilbene being the more stable of the two. On the other (9) This prediction rests on the argument presented earlier that hand, with X = +N(CH3)3,the threo isomer can be diastereomer A should be more stable than B (L = large, M = medium expected to be more stable than the erythro since L‘ L‘ +N(CH3)3is probably effectively more bulky than a sesses certain advantages for the study of particularly the latter problem. The mechanism of the transformation is known,5 and the great energetic preference of the reaction for assuming a trans steric course has been thoroughly established.6 The relative thermodynamic stability of the starting materials (diastereomers) can be estimated and that of the products (geometric isomers) can be determined. Thus, the relative rates of the E2 reaction as applied to diastereomers allow the geometry of the transition state to be identified as being more like that of the starting material or of the product with regard to steric effects.’ The 1,2-diphenyl-l-propyl-X system (I) was chosen for this investigation for the following reasons : (1) the diastereomeric starting materials are crystalline and can be prepared with X as a number of different leaving groupss; (2) the cis-trans-olefinic products (11) are easily identified since they are crystalline and possess different ultraviolet absorption spectrasa; ( 3 ) the elimination can go in only one direction, and the transformation occurs with the virtual exclusion of substitution reaction.
+
(5) M. L. Dhar, E. D . Hughes, C. K . Ingold, A. M. Mandour, G. A. Maw and L. I. Woolf, J. Chem. SOC.,2093 (1948). (6) (a) Ref. 2a and 2b; (b) P. Pfeiffer, Ber., 46, 1815 (1912); (c) S. Winstein, D . Pressman and W. G . Young, THISJOURNAL, 61, 1645 (1939); (d) S. J. Cristol, ibid., 69, 338 (1947). (7) G . S. Hammond [ibid., 77, 334 (1955)j has recently made a qualitative correlation between the rate, the thermodynamics and the geometry of transition states of reactions. (8) (a) D. J. Cram and F. A. Abd Elhafez, ibid., 7 4 , 5828 (1952); (b) 1 4 , 5851 (1952); (c) 76, 339 (1953).
L A
L H
and S = small groups in a relative sense). Three experimental tests of the argument have been consistent with this generalization [see ref. 8c and D. J. Cram and F. D. Greene, THISJOURNAL, 76, 6005 (1953) I.
Vol. 78
792 TABLE I RATESO F ELIMINATION REACTION O F 1,2-DIPHENYL-l-PRoPYL-X
Tyw, Run
C. 50.02
Solvent
Basea concn., moles/l.
,
Alkyl-X
X
Config.
7
Concn., mole/l.
V0 yld. olefin
kEa,b
liters moles - 1 sec. -1
1.282 c1 threo 0.0643 74.94 CkH50H 96 4.47 f 0.06 X 74.94 CzHsOH thveo 98 4.50 f .08 X 1.915 c1 ,0688 I.915 c1 threo 98 3 . 2 9 f .04 X 49.87 CzH60H ,0688 1.143 c1 erythro ,0348 100 4.32 f .03 X 74.94 C2H50H c1 2.325 erythro ,0675 100 4.32 f .04 X 74.94 CoH50H c1 erythro ,0677 2.016 100 2.96 =t .03 X 49.73 CtHsOH 0.4966 c1 75.07 n-C~Hi70H thveo ,0685 90 2.83 =k .04 X tlweo 75.07 n-CsH17OH ,849 c1 90 1 . 4 1 =k .01 X ,0690 ,927 c1 ,0708 threo 75.07 n-CsH170H 89 1.14 f .02 X Cl erythro ,849 .0672 75.07 n-CsHi;OH 99 1.51 =t .03 X ,927 c1 ,0381 erythvo 75.07 n-CsHirOH 1.25 .02 x 10-6 98 c1 threo ,07304 75.02 n-CsHiaCHOHCHs 1.082 96 1.80 .03 X 1 O - j ,07504 lac 75.02 n-CeHlaCHOHCHa 1.082 c1 erythro 100 5.10 =t .05 X threo 14d c1 0.604 ,0674 75.00 (CH3)3COH 94 3 . 7 6 f .20 X 15d threo ,865 c1 ,0543 75.00 (CH3)3COH 92 4.50 f .04 X 16d threo .Os44 93 2.93 i .03 X 49.60 (CH8)aCOH ,865 c1 17d eiythro ,7704 c1 75.00 (CH3)sCOH ,0688 90 4.04 =t .09 X 18d erythro ,0686 ,9232 c1 75.00 (CH3)zCOH 91 4.37 i .07 X 19d rrytlzro 75.00 (CH3)aCOH 1.280 Cl 0683 90 5 . 5 5 i .07 x 10-8 20d czr yt h i o 0.9232 c1 ,0685 99.50 (CH3)sCOH 90 5.14 f .04 X ,0686 21d 100.80 (CHs)3COH c1 r(,ythio 90 '7.45 =t , 2 5 X 10-5 1.280 22e thieo ,06925 9.1- 3.10 j= .03 x 10-5 0.8866 c1 75.00 ( CHB)~COH erythro 236 1.130 c1 75.00 (CH3)aCOE ,07337 87 8.57 i .10x 10-6 24d threo . OB934 75.08 CzHs( CH3)zCOH 0.7002 c1 83 4.95 i .09 x 10-5 25d erythvo ,06934 ,7002 c1 82 4.60 =t .08 X 75.08 CnHs( CH3)2COH 26' thieo ,0679 ,1236 c1 74.96 C6H6 . .',i 3 . 3 3 i .42 x 10-4 27f e r yt h r o ,0679 . . o r 1 6.34 rt 1.10 x 10-5 ,1236 c1 74.96 C ~ H E threo ,0369 . .osk 2 . 1 0 =t 0.04 x 10-4 ,612 Br 50.01 C ~ H ~ O H - C ~ H E 28 ,0369 f10.01 C?HbOH-C& crythio ,612 Br . . o s L 3 . 0 3 i . i o x 10-4 29 thveo ,5673 Br 94 6.58 f .14 X 10-6 ,0369 50.00 (CHa)jCOH 30 evyth YO 0360 50.00 (CH3)iCOH ,5673 Br 93 1.22 i .04 x 10-5 31 +11'(CH3j3 thrco 00507 1.220 93 1.07 ~t.02 x 10-3 74.84 CoIi50H 32h ,0262 1.220 -S(CH3)3 erythio 74.84 C2HjOH 33" 89 1.88 i .13 X ,528 X 10Y3 100 4 . 2 6 i .23 X 0.5070 -i\'(CHa)s thieo 34drh 30,OO (CH3)aCOH ,418 X 98 3 . 9 1 i . 2 1 X lo-' 0.5070 +N(CHa), evythro 35'3Ph 30.00 (CH3)aCOH a Runs 1-11, 28, 29, 32 and 33, sodium alcoholate (see solvent) employed; runs 12-21, 24, 25,30,31,34and 35, potassium alcoholate (see solvent) used; runs 22 and 23, CPHIOKand runs 26 and 27, n-C6H13CHOKCH3used; concn. a t 25'. * Pseudo first-order rate constant followed by Yolhard method except where indicated. Corrected for solvent expansion (see Experimental) except in runs 26 and 27 and those conducted a t 30" (runs 34 and 35). Also corrected to the amount of olefin produced. k~~ based on lllyc of olefin. Results from a small amount of cis + trans. d trans-Olefin was main product. -411 other reactions stereospecific, threo + trans, erythro -+ cis. Equivalent amount of absolute ethanol added to (CH3)3COH[(CH3)aCOK = 1 equivalent]. f True second-order rate coxistarits are reported. Rate constants decrease in value with time and are between second and third order. 0 Benzene prevented ultraviolet analysis of olefins. Olefins were isolated, thveo + trans and erythro -.+cis. I n runs 28 and 29, benzene had to be added to solubilize the bromides; proportions Runs followed spectrophotometrically. Yield trans-olefin, 93%. employed: 33 ml. of ethanol to 23 ml. of benzene. j Yield cis-olefin, 87yC, Yield trans-olefin, 1 0 0 ~ c , . Yield trans-olefin, 9Syc.
1
2 3 4 5 6 7 8 9 10 11 12
Amax 273 mp ( E 19,900'1,lO the amount of olefin produced as well as its character could be determined. Product isolation experiments were carried out in experiments duplicating the conditions of runs 15, lS,2 6 , 2 T , 28, 29, 3 2 and 33 (Table I). The poorest yield of olefin indicated spectrophotometrically was S6Y0, and the average was 9GYG The poorest yield of olefin isolated was 8 3 7 . Those reactions involving a primary or secondary alkoxide as base clearly assumed a trans steric course, the tlireo isomer giving trans- and the erythro the cis-olefin. The two runs (30 and 31) conducted a t 50" with potassium t-butylate and the alkyl bromides were also stereospecific in the same (10) T h e ultraviolet spectrum of each olefin is recorded in ref Sa I' he differences in t h e shapes of the curves allow t h e t w o olefin? t o be easily differentiated
*
sense. However, in those runs conducted a t 75" (or above) in t-butyl alcohol with potassium t-butylate as base, the erythro-chloride gave predominantly irans-olefin (runs 17-21). Under the conditions of the experiment cis-olefin was found to isomerize largely to the trans. In an experiment with erytlzrochloride, t-butyl alcohol and potassium t-butylate (88') which was interrupted after one half-life, a t least 20% of the olefin possessed the cis configuration. I n view of these results, it is highly probable that the erythro-alkyl chloride gave cisolefin which was subsequently isomerized to the tmns. I n contrast, the erythro quaternary a i n n i o nium salt in t-butyl alcohol with potassium t-buty-late (run 35) gave only trans olefin a t a temperature (30") a t which cis olefin was demonstrated to persist.
ECLIPSING EFFECTS IN
Feb. 20, 1956
RATIOSO F Runs comp.
E2 REACTION
793
TABLEI1 ELIMINATION RATESO F DIASTEREOMERIC 1,2-DIPHENYL-l-PROPYL-X
X
+ + + + + + + + + +
THE
Temp.,
OC.
Solvent
Base
kEz thrco/
kE, erythro
0.76 Br 50 CzH60H-CeHe" CZHsOiYa 28 29 1.1 c1 50 CzH5OH C2H60Na 3 + 6 5.4 Br 50 (CH3)3COH (CH3hCOK 31 30 c1 EO (CHahCOH (CHa)aCOK 15" 16 - 21 57 +N(CHzh 75 CzHsOH CzH50Na 33 32 1.0 c1 75 CzHsOH CzH60Xa 2 + 5 O.!? c1 75 X-C~HI~OH n-CsHl,OKa 8 10 3.5 c1 75 n-CsHiaCHOHCHa n-Cd313CHOKCH3 12 13 -5d c1 75 C6Hs n-CsHlsCHOKCH3 26 27 10.6' c1 75 (CH3hCOH (CHa)aCOK 15 17 - 19 CZHEOK -4f c1 75 (CH3)aCOH 22 23 10.7 c1 75 CyHa( CH3)zCOH Cz&( CHa)zCOK 24 25 1.10 35 34 +N(CH3)3 30 (CH3)aCOH (CHa)&OK a Benzene employed (40% by volume) to solubilize the bromid-3. Ratio based on pseudo first-order rates, not corrected k E z threo for run 16 is for amount of olefin produced. Isolation expximents indicated a t least 85% yield in each case. employed. kE, erythro is calculated for 49.63' and a bas: csncentration the same as for run 16 (0.865 M) as follows. A plot of k E n erythro us. base concentration a t 75' is virtually linear, and a rate of 4.26 X 10" 1. mole-' sec.-l can be inferred for kxZ erythro a t 0.865 Jf base a t 75". Utilizing runs 18 and 23 (base = 0.9232 M ) , A H can be calculated, and using thew Ratio only approximate since rates are of values, kEI erythro a t 0.86
