March 20, 1960
AIETALHYDRIDE REDUCTION OF KETOXES AND
T h e product gave negative tests for halogen and a positive test for olefinic unsaturation with tetranitromethane. I t s infrared specbrum showed a band at 6.1 p and the absence of bands a t 5.8-6.0 f i . Analysis of Products .-Preliminary qualitative analysis of all products was made by comparison of infrared spectra with spectra of authentic samples. When the physical constants and the spectrum of the product indicated a pure compound had been obtained, a characteristic derivative generally was prepared and compared with an authentic sample. Authentic samples of the carbinols listed as products in Tables 1 and I1 were commercial materials except: 3,3-dimethyl-2-butanol by the LAH reduction3*of pinaco1-chloro-2-propanol by the L h H reduction40 of chloroacetone,413-phenoxy-1-propanol by the reaction of sodium phenoxide with trimethylene chlorohydrin,“ l-phenoxy-2propanol by LAH reduction of l-phenoxy-2-propanone, 2,4,4-trimethylpentanol-3by the reaction of isobutyraldehyde and t-butylmagnesium chloride,43and cyclopentplcarbinol by the LSH reduction of cyclopentanecarboxyaldeh ~ d e . ~Samples * of 2,4,4-trimethylpentanol-l,2,4,4-trimethylpentanol-2 and 2,2,3,3-tetramethylbutanol-l were not readily available and these products were characterized through suitable derivatives. Ix’hen a mixture was obtained, the product was analyzed quantitatively by mass s p e ~ t r o m e t r yor ~ ~by vapor phase chromatography. The vapor phase chromatographic analysis mas carried out on a ITilkens Aerograph instrument in conjunction with a Brown Electronik recorder. Helium was (38) Cf. A. A. Bothner-By, THISJ O U R N A L , 73, 846 (1951). (39) G. A. Hill and E. W’ Flosdorf, ref. 25, p. 4G2. (40) C. A. Stewart and C. 4 . ‘b7anderWerf, THISJ O U R N A L , 76, 1259 (1954). (41) E. R. Buchanan and H . Sargent, ibid., 67, 400 (1945). (42) S. G. Powell, ibid., 46. 2708 (1923). (43) F.C. Whitmore and A. L. Houk, i b i d . , 64, 3714 (1932). (44) A generous sample was supplied by Professor George F. Hennion, University of Notre Dame. (45) Cf, E . L. Eliel, T. J . Prosser and G . W.Young, J. Chem. E d . , 34. 72 (1957), and literature there cited.
[CONTRIBUTIOX F R O M
THE
-%LCOHOLS
13Gi
used as the carrier gas maintained at 8 p.s.i. at flow rates of 60-100 ml. per minute. Components were identified by comparison of their retention times with the retention times of authentic samples. When necessary components were collected and identified by infrared spectroscopy. Areas under the peaks were measured with a planimeter and the mole ratio of components calculated from area ratios. Authentic mixtures were analyzed in all cases to verify the assumption t h a t peak areas were proportional to mole ratios. Table I11 gives the epoxide reduced and the substrate and temperatiire used for an efficient separation of the products obtained as shown in Tables I and 11.
TARLE I11 CONDITIONS FOR S‘APOR PHASE CHROMATOGRAPIIIC XNALSSES Products from Substrate T,O C . Tetramethylethylene oxide Ucon-polar S8-89 Epichlorohydrin Tide detergent 100-105 a-Methylstyrene oxide Tide detergent 17 a-Diisobutylene oxide Ucon-polar 129 @-Diisobutyleneoxide Ucon-polar 129 Cyclohexene oxide Ucon-pcilar 139
Acknowledgment.-This work is a contribution from the Radiation Project of the University of Notre Dame, supported, in part, under Atomic Energy Commission contract AT( 11-1)-38 and Navy loan equipment contract Nonr-06900. We are indebted to Professor V. J. Traynelis and Dr. Zoltan Welvart for helpful suggestions. The vapor phase chromatographic equipment for this investigation was acquired under National Science Foundation Grant G-4058. NOTRE
DAME, I K D .
CHEXICAL LABORATORIES O F THE UNIVERSITS O F NOTRE DAME]
Reduction with Metal Hydrides. VIII. Reductions of Ketones and Epimerization of Alcohols with Lithium Aluminum Hydride-Aluminum BY
ERNEST
L. ELIELAND MARKN. RERICK RECEIVED JULY 28, 1959
Whereas lithium aluminum hydride (LAH) reduced 4-t-butylcyclohexanone to a mixture of 90% trans-4-t-butylcyclohexanol (I) and 10% cis-4-t-butylcyclohexanol (11), LAH-AICI3 (1 :4ratio) yields 80% trans- and 20% &alcohol under kinetically controlled conditions. Addition of excess ketone or acetone at the end of the reaction leads t o thermodynamic control of the reaction products with conversion of the alcohol mixture to one containing over 99% of the trans isomer in less than fifteen minutes. The fast reaction and overwhelming preponderance of the trans isomer is ascribed to the nature of the species equilibrated which are bulky aluminum complexes, not readily accommodated in the axial position of the cyclohexane ring. The equilibration procedure has been utilized to determine the conformational equilibrium values for methyl and phenyl groups. The conformational free energy differences (A-values) are 1.5 =t0.1 kcal./mole for methyl and ca. 2.6 kcal./mole for phenyl.
There have been several recent papers3 indicating that the reducing action of LAH-AICI3 combinations differs from t h a t of LAH alone. For example, in our own laboratories we have observed that epoxides may be reduced in a different way by LAH-AIC13 than by LAH alone2t4 and that acetals, unaffected by LAH, are reduced to ethers (1) Presented in part a t the S a n Francisco xational Meeting, ~ m Chem. SOC., April 14, 1958. (2) Paper V I I , E . L. Eliel and M . N. Rerick, THISJ O U R N A L , 83, 1362 (1960). (3) For a summary, see M . N. Rerick, “Selective Reductions of Organic Compounds with Complex Metal Hydrides,” Metal Hydrides, Inc., Beverly, Mass., 1959. ( 4 ) E. L. Eliel and D . W. Delmonte, THIS J O U R N A L , 80, 1744 (1958).
by the “mixed reagent.”j Wheeler and Mateos6 have reported that cholestanone, reduced to a mixture of 88% 3-/3-hydroxycholestane (equatorial OH) and 12% 3-a-hydroxycholestane (axial OH) by LAH, gives exclusively the beta (equatorial) isomer with the mixed reagent. The need for substantial quantities of trans-4-t-butylcyclohexanol(I, equa. torial hydroxyl) in other Work prompted us to try to apply this reduction to the commercially available 4-t-butylcyclohexanone. ( 5 ) E. L. Eliel and hl. S. Rerick, J . Ovg. Chem., 23, 1088 (1958). See also E . L. Eliel and V. G. Baddiny, THIS J O U R N A L , 81, 6087 (1959). ( 6 ) 0. H. Wheeler and J. L. Mateos, Chemistvy B I n d u s t r y , 395 (1927); Ca;z. J . C h i n . , 36, 1431 (1958).
1368
ERNESTL. ELIELAND MARKN. RERICK
VOl. 82
the result of the reduction of this ketone with LAH or AlH3 (entry 4) means t h a t equatorial /-.-”.()II 1 m d axial alcohols are produced in a S.9:l.l ratio whereas LAH-A1Cl3 (entries 1-3) produces these ( C w & - J ( C m J - 4 alcohols in a 8:2 ratio. I n 4-methylcyclohexaI 11 none, based on the experiments t o be discussed Somewhat to our surprise, the reduction of 4t-butylcyclohexanone with t h e mixed reagent gave below, it appears that 92% of the molecules have less trans-4-t-butylcyclohexanol (I) than reductirni equatorial methyl substituents and 8y0 have axial with LAH alone. The same was true of 4-methyl- methyl substituents.lo The former (e-CI13 kecyclohexanone and 4-phenylcyclohexanone, The tone) should give rise t o 92 X 0.S9 or S2% epertinent results are summarized in Table 1. CHi3-e-OH ( i e . , trans) alcohol and 92 X 0.11 or Interestingly enough, the changed proportion of 10yo e-CH3-a-OH (i.e., cis) alcohol. T h e latter the products is observed not only with a 1:3 or 1 :I(a-CH3 ketone) should give rise t o 8 X 0.89 or 7% ratio of LAH to A1C13 (entries 2 , 1, reagent pre- a-CH3-e-OH (i.e., cis) alcohol and 8 X 0.11 or sumably AlHC12) but also with a 1:l ratio (entry 1% a-CH3-a-OH (i.e., trans) alcohol. Thus the 3, reagent presumably AlH2Cl). On the other predicted percentage trans-4-methy-lcyclohexanol 1 or 83% and the predicted perhand, with a 3 : 1 ratio of LAH to AlCl, (entry 4, formed is S2 centage cis-4-methylcyclohexanol is 10 7 or 17%. presumed reagent AlH3) the proportion of cis- and These percentages would appear to agree, within trans-products is the same as with LAH alone the limit of combined experimental error, with the (cntry 5). experimental finding of 79-8170 trans (Table I, TABLE I entry 6). Similar considerations, applied to the REDUCTION O F ~-L%LKYLCYCLOHEXASONESTVITH LiXIH4reduction of 4-methylcyclohexanone with mixed AICll hydride, lead to a prediction of 75% trans- and 25% LAH.” AICh,” Yield, cis-4-methylcyclohexanol product in good agreeRun Cyclohexanone mole moles % frans,b % ment with the experimental 76-7770 trans (entry 1 4-&Butyl0.275 1.0 95 78-83 7). For 4-phenylcyclohexanone, assuming the 2 4-t-Butyl.275 0.75 96 79-83 phenyl group to be axial in 98.5% of the niole3 4-t-Butyl.275 .25 88 79 cules (see below) the agreement is not as good: 4 4-&Butyl,275 ,053 96 88-89 87.5y0 trans-4-phenylcyclohexanolpredicted z’s. 5 4-t-Butyl,275 .O 99 88-9OC 90-91% found (entry 6) in the straight hydride ii 4-Methyl,278 .0 7t; 79-81d reduction and 79.5% trans predicted 8s. S5-S6% 7 4-Methyl,275 1.1 93 76-77 found (entry 9) iii the mixed hydride reduction. .30 8 4-Phenyl0.0 89 90-91 This may mean that either the fundamental steric 9 4-Phenyl,312 1 25 99 85-86 assumptions are particularly poor for the phenyl a Sormalized t o one mole ketone; most runs were carried group or, perhaps more likely, that the phenyl nut o n one-tenth this scale. * Analyses by infrared and/or group introduces a disturbing polar influence. l 1 vapor phase chromatography; the range indicates the reproducibility of tile analyses. o Ref. 7 reports 9l-93Y0; The experiments so far discussed failed in their the present figure probably is more accurate. Kef. ’7. original purpose to produce pure I. However, in The rationale of product composition in the one reduction of 4-t-butylcyclohexanone with reduction of ketones to a mixture of epimeric al- LAH-A1C13 we did obtain nearly pure I. n‘heri cohols by metal hydrides has been discussed else- this matter was investigated in detail, i t was found where.8 It is of interest t h a t “product develop- that, fortuitously, an excess of 4-t-butylcyclohexment control,” i.e., forniation of the more stable anone was present in this particular run. Deproduct (in the present case the trans isomer) is liberate use of an excess of ketone (Table IT, run 10) produced almost isonierically pure I. Esmore marked with LAH alone than with t h e LAHXIc13 reagent. This may be because t h e “mixed sentially the same result was obtained (Table 11, reagent” is more bulky and therefore somewhat runs 1 and 2 ) by adding acetone at the end of the more prone than LAH alone to approach from the reduction and allowing the mixture to boil for 15 less hindered (equatorial) side t o give t h e (less minutes. It was evident t h a t this led to a change stable) cis isomer. I n this respect, the “mixed in product composition to nearly pure trans reagent” appears to resemble sodium borohydride isomer after r e d i d o n was cornplPte; aliquots of the which previously has been shown8 to be subject reduction product removed prior to the addition to “steric approach control” t o a greater extent of acetone showed the usual 80-20 composition. than L h H . The greater bulkiness of reagents (Compare runs 1 and 2 in Table T with the corsuch as hlHCl2 and AlHzCl as compared with responding runs in Table 11; these refer to the NH4- may be in part due to the size of the chlorine same reaction, part of which was worked up prior atoms and in part t o the fact t h a t tricovalent (10) I t is aswmed here t h a t the change from tetrahedral geometry aluminum is strongly coordinated with solvent n t carbon 1 i n methylc)clohexane t o trigonal geomrtry a t carbon 4 in ether molecules. 4 methylcyclohexanone does not affect the conformational equilibrium If one assumes that t h e t-butyl group in 4-t- of the methyl group. Recent work by R A , Benkeser and E . W RenTHIS JOURNAL, 80, 3414 (1958). casts some doubt on t h e rorrectbutylcyclohexanone and t h e corresponding alco- nett, ness o f this assumption. Further work undouhtedlv is required to hols is entirely in the equatorial p o s i t i ~ n ,then ~ indicate how good (or had) this assumption is and t h e calciilotions OH
)
+
( 7 ) E. I,. Eliel and R. S. Ro, THISJOURNAL, 79, 5992 (1957). 18) W. G D a n l x n , G. J. Fonken and D. S. Noyce, ibid., 78, 2579 ( 1 9 iii).
(9) S. \Vinslrin and S . J. Holnrss, ibid.. 77, 55(32 (19~~.>1.
+
here are presented because they have a bearing on this point. 111) Diffirnlties dire t o polar effects of phenvl have been encountcreri previouill- E . I. Iilirl and C . A . I.uknch. ( I 93il
March 20, 1960
TABLE I1 EPIMERIZATIONS AND ATTEMPTEDEPIMERIZATIOSS O F 4-AI,KYI,CYCLOHEXASOL.S Run
1369
METALHYDRIDEREDUCTION OF KETONES AND ALCOHOLS
Starting material
LAH," mole
AICI3,moles
Ketone addedb
WITH
Ili.llf~~-.\lcl~
Yield,c %
tvnns,d
%
94 99-10O6 0.834 NU 95 98-99" 1.0 Yes, h 0.73 Yes, .1 96 92-9,ie Yes, A 55 78-81e 3' .25 Tes, .\ R,5 88-90' 4 ' , os3 \-;es, A 93 89-91e 11 .0 1.25 1-0 99 95-96 12g 1 0 Fob 93 52--83 13 14 ,275 1.0 Yes, X 96 9ij-9;* 1.0 Yes, B 91 81-?2 15 .0 K O 91 95-99 16 ,275 1.0 Yes, n;I 92 91.0* 17 4-Methylcyclohexanol j ,275 1.1 Yes, M 87 92.5-93,Z" 18 trans-4-Met hylcyclohexanol ,275 1.0 19 4-Phenylcpclohexanc,Ik Yes, P 87 97.7-98. le . 3 12 1.25 'T.'es, P 80 99.1-99. 2e 20 trans-4-Phenplcyclohexanol ,312 1.25 Ketone (-4 = acea Normalized t o one mole of starting material; most runs were carried out on one-tenth this scale. tone, B = 4-t-butylcyclohexanone, M = 4-1nethylcyclohexanone, P = 4-phenylcyclohexanone) added at the end of the Trace amounts of ketone in the product completion of the reaction of starting material and the reagent; see Experimental. Out of total alcohol produced, disregarding any ketone; analare not taken into account in the calculation of the yield. yses by infrared and/or vapor phase chromatography. The range indicates t h e reproducibility of the analyses. E Parent ketone also present. f Split run; a n aliquot of the reaction mixture was worked up before addition of ketone t o give the products shown in Table I. Excess ketone was added to the remainder and worked up to give the products shown herein. ii Methyl acetate used in place of acetone. Mixture of 81% 0 Inverse addition of the mixed hydride solution to ketone. trans and 19% cis. j Mixture of 770%trans and 23% cis. Mixture of 79% trans and 2157, cis. 10 1' 2'
4-t-Butylcyclohexanone 4-t-Butylcyclohexano1ie 4-t-Butylcyclohexanone 4-t-Butylcyclohexanone 4-t-Butylcyclohexanciiie 4-t-Butylcyclohexanone 4-t-Butylcyclohexnnme 4-t-Butylcyclohexanone 4-t-Butylcyclohexanol' 4-t-Butylcyclohexanol~ trans-4-t-Butylcyclohexanol
0.229 .275 ,275 .27,5 .27j .27B ,344 .27.5
to the addition of acetone and t h e remainder following the addition of acetone and 10-15 min. boiling.) It also was noted t h a t when acetone was added at the end of t h e reduction, 4-t-butylcyclohexanone (which had been completely consumed in t h e reduction) was regenerated. As a result of these experiments, it became clear t h a t t h e complex formed from 4-t-butylcyclohexanone upon reduction with LAH-AlC13 undergoes a rapid equilibration of the Xeerwein-Ponndorf-Oppenauer type'? in the presence of excess ketone (4-t-butylcyclohexanone or acetone). The position of the equilibrium is almost entirely on the side of t h e trans complex. The equilibrating complex may be generated starting with a mixture of 4-t-butylcyclohexanols (rather than the ketone), as shown in Table 11, run 14. Not unexpectedly, inverse addition of the mixed hydride solution to the ketone (run 12) results in a product close to the equilibrium mixture, since under these conditions ketone is present in excess throughout the reduction and equilibration may occur concomitant with reduction. T h a t a true equilibration rather than destruction of t h e cis isomer is involved follows from run 14, Table 11, in which a 4-t-butylcyclohexanol mixture containing 20% cis isomer gave nearly pure trans isomer in 96% yield. Even more convincing in this respect is the evidence embodied in runs 17 and 18 where equilibrium (corresponding to ca. 92yo trans-4-methylcyclohexanol complex) was reached from both sides. Several aspects of the equilibration are of interest. One concerns the conditions of the equilibration. It is necessary, as in other equilibrations o f the XLIeerwein-Ponndorf-Oppenauer type, t o (12) Cf. A. L. Wilds in R. Adams, "Organic Reactions," John Wiley and Sons, Inc., New York, X , Y., Vol. 2, 1944, Ch:ip. 5 ; and C. Djerassi, ibid., Vot. 6, 1951, C h a p 5 . (13) Cf. W. v. E. Doering and T . C. Aschner, THISJOURNAL, 71, 838 (1949); also refs. 7 and 8.
have ketone present. Excess alkylcyclohexanone or added acetone seemed equally effective in the equilibration of the 4-t-butylcyclohexanol complexes, but equilibration of 4-phenylcyclohexanol and 4methylcyclohexanol complexes proceeded readily only in the presence of an excess of the corresponding ketone. In these cases attempted equilibration with acetone did not proceed to completion and led to discoloration of the reaction mixture, possibly due to the formation of condensation products. Addition of methyl acetate instead of ketone a t the end of the reaction (run 13) fails to produce equilibration. The ratio of aluminum chloride to lithium aluminum hydride in the "mixed reagent" is of crucial importance. No equilibration occurs, even in the presence of added acetone, with A1Cl4:LAH ratios of 1:l and 1:3 (Table 11, runs 3 and 4) nor is equilibration by acetone effected in the absence of aluminum chloride altogether (Table 11, run 11). A 3 : l ratio of chloride to hydride does produce equilibration (Table 11, run 2 ) , but a 4 : l ratio is even more effective (Table 11, run 10) and is recommended for all practical purposes. The reagent present a t a 3:1 ratio of chloride t o hydride is probably'? XIHClz LiAlHd
+ 3AIC13 +LiCl f 4.11HC12
and the equilibrating species may thus be ROA1C12. The fourth mole of aluniinuni chloride may merely ensure t h a t this material is really present in adequate stoichiometric amount, or i t may actually perform a function of its own in the equilibration. No isomerization was produced by aluminum chloride in the absence of lithium aluminum hydride (Table 11, run 15). The time and temperature conditions for the equilibration are quite remarkable. I n the case of 4-t-butylcyclohexanol, equilibration is substan(14) E. Wiberg and M. Schmidt, Z . A'a2zi~joi.srh., 6b, 4iiO (1951).
ERNEST L. ELIELAND MARKN . RERICK
Vol. h:!
.A
'
-
complex ("
>c /uio\-
complex
?ig. ? . Eqrtilibrritiriri (,I 4-t-littt~-l 1ohe:;n:iol ~
-? (13
/:,Ill
Icyclohexand \vas obtained by ga3 chrumatographic ~ n u l y . i , of an equilibrium mixture obtained in the course of another invcstig:rrion (ref. 7 ) and supersedes t h e previous vnliie (ref. 5 ) oi " i o z S ( 7 " ti:rscd on a v e r y crude infrared analysis, ( T h e - ~ - g l i e n ~ - I c ~ - i l l o h c x a ndo r i lnot ~ have intense distinctive infrared hands suitable for alial)-.is.) I 18) Srldium o r aluminum salts of the alcohols t o be equilibrated ill be yrssent in onlr vcry small concentration, since they are in equi. librium with t h e free alcohols and t h e sodium (or aluminum) salts of isopropyl or t-Liut\-l d c o h u l . 119) T h e situation here resembles t h a t in t h e isomerization of the xylcnes i n liyiirog.cn fluoride solution by boron trifluoride. The i.I 2 ) , have shown t h a t a t low BFs t o xylene ratio, an equilibrium mixturc corresponding t o t h e thermodynamic stability oi the t h e ? xylenes is ohtained; b u t a t a 1:l BFI to xylene ratio t h e equilibrium mixture corresponds t o nearly pnre m-xylene because this isomer forms by fur the most stable €IF-BFI complex.
Pig. 2 . - E q i r i ! i l J m t i ~ ~ ~oi f : ~ l k y l c
In agxcnieiit with this is the observaLioii that cis-4-t-butylcyclohesanoi is equilibrated much more rapidly than the other two cis-4-alkplcycloheranols with which we worked. Steric crowding of the -0-IIC12 group in the axial position evidently makes the axial isomer quite niist:th!.,: and, a t the same time, produces a strong steric ucceleration tci isomerization. The energetic situation is depictrtl in Fig. 1. The situntio!i with the other alkylcyclohexanol complexes is more coniplicated because their alkyl substituents (unlike the 4-f-butyl groupg) are not constrained to the equatorial position. The conformational situation is depicted in Fig. '3. The t r a m isomer is nearly exclusively in the equatorialequatorial conformation. Upon equilibration, the -0=11Clz group is to some extent forced into the axial position, but the resulting -4-forrn of the cis isomer (Iluirin.g' A 'Tide detergent culumn was used for tile aiulysis of cis atlJ tru,7s isoiiiers of I-t-butylcyclrJiieuani,l' an6 4-~~iie~iyicye~olie~aii~11. Analysis of mixtures of the furmer containing less tlian 4' omer and mixtures of tlie latter ctnitairiing less tliaii cis isomer were found to be more accurate after prereiiiovnl of any ci~nt:trnitiatiiig ketwie if it \vel-? present.
Acknowledgment.-This work is a contribution from the Radiation Project of the University of Notre Dame, supported, in part, under Atomic Energy Commission contract AT(ll-I)-XS and Navy loan equipment contract Nonr-06900. The vapor phase chromatographic equipment was acquired under National Science Foundation C,r:~nt G-4-5S, SOTRE DAME,IND. (27) Preparcd according to the m?thorl uf 13. I,. 131iel and C . A. I.nkach, Tars J O U K U A I . . 1 9 , 5980 (19.57). (28) I
