Vol. 33, No. 1.1, November 1968
CONFIGURATION OF SUBSTITUTED
same way. An analytical gas chromatogram of the resulting ester mixture showed relative peak areas of about 33 to 67. The mixture of diastereomeric esters was spearated from extraneous impurities by preparative glpc (SF-96 silicone column, in. 190', helium flow rate 100 ml/min, retention time 6 ft x 10 min, one peak) to give 0.37 g which was reduced with lithium aluminum hydride, hydrolyzed, and distilled to give 0.29 g of a carbinol mixture which was separated by glpc (SE-30 silicone column, 20 ft x a/* in. 200', helium flow rate 75 ml/min) to give phenyltrifluoromethylcarbinol { retention time 16 min; 10 mg; ~ * S D -0.26 f 0.02' (c 2.0, chloroform, 1 = 0.5); [LY]=D -25 f 2" (c 2, chloroform)) and 2-methoxy-2-phenylethanol D f 0.01' (c 5.15, {retention time 36 min; 26 mg; ( Y ~ ~-1.89 ethanol, I = 0.5); [aIz8~ -73" (c 5.15, ethanol)). The rotation of the volatile phenyltrifluoromethylcarbinol was determined on a very small amount of material, and the indicated racemization of 15 f 6% may not be significant, but the latter compound is clearly racemized to the extent of approximately 35% as shown by the following experiment. ( - )-2-Methoxy-2-phenylethanol.-O-Methylmandelic acid { 1.O g; [aIz6~ -144' (c 1.2, ethanol); 96% enantiomerically pure) was reduced with lithium aluminum hydride, and the (-)-2methoxy-2-phenylethanol was isolated and purified as above to
TRIFLUOROMETHYLCARBINOLS 4245
give a product with d 7 D -134.78" (neat, 1 = 1); $JD -8.17 f 0.02' (c 6.425, ethanol, = 1); [ ( Y ] ~ @ D-127.0 f 0.4' (c 6.4, ethanol). Partially Active (+)-Methyltrifluoromethylcarbinol.-LMethyl t,rifluoromethyl ketone (7 g) was treated with 65 ml of a 0.93 N solution of the Grignard reagent from (+ )-l-chloro-2-phenylbutanes [ a a 7 +5.68" ~ (neat); 96% enantiomerically pure] in ether a t 35". The reaction mixture was processed in the usual way and distilled to give a 63y0 yield of (-)-methyltrifluoromethylcarbinol which upon purification by gas chromatography -2.20" (neat, 1 = 0.5). A second experiment using had CPD twice these amounts gave material after purification of d 4 -2.03" (neat, 2 = 0.5). Esters from (+)-, (-)-, and (i)-Methyltrifluoromethylcarbinol and ( )-0-Methylmandelic Acid.-The preparation and gas chromatography of these have been previously described.l
-
Registry No.-Phenyltrifluoromethylcarbinyl 36: acetoxy-A5-etienate, 17628-68-1; ( - )-IA, 10531-50-7' (+)-IA, 340-06-7 ; t-butyltrifluoromethylketimine' 17629-00-4; (+)-IB, 17628-71-6; (-)-2-methoxy-2phenylethanol, 17628-72-7; (+)-IC, 17628-73-8.
Absolute Configuration of Substituted Trifluorornethylcarbinols1~' HOWARD M. PETERS,3 DOROTHY 31. F E I G L , 3 a
AND
HARRY 8. h f O S H E R
Department of Chemistry, Stanford University, Stanford, California 94306 Received April 88, 1968 By application of Freudenberg's rule of rotational shifts as applied to a series of acetate, benzoate, and acid phthalate esters, the absolute S configuration was assigned to (+)-phenyltrifluoromethylcarbinol, ( - )-methyltrifluoromethylcarbinol, and ( - )-t-butyltrifluoromethylcarbinol. However, these correlations were not ideal, and thus the absolute configurations of the phenyl and methyl compounds were verified by synthesis of their 0-methyl and 0-ethyl ethers by the action of sulfur tetrafluoride on (S)-0-methylmandelic acid and (S)-0-ethyllactic acid, respectively. This process is one which does not affect the chiral center of known configuration. The absolute configurations of these trifluoromethyl compounds and their several derivatives are now established with certainty.
I n order to gain additional information concerning the relative importance of steric vs. electronic effects in the Grignard asymmetric reduction r e a ~ t i o n ~we - ~have been studying the asymmetric reduction of several substituted trifluoromethyl ketones. The previous paper in this series0 describes the resolution of three such compounds : phenyltrifluoromethylcarbinol, methyltrifluoromethylcarbinol, and t-butyltrifluoromethylcarbinol. The present paper describes studies which establish the absolute configuration of these compounds. We initially investigated5 the application of Freudenberg's rule of rotational shifts'o to a series of derivatives of these carbinols and compared the results with those from the corresponding nonfluorinated carbinols of (1) Presented in part before the Division of Organic Chemistry a t the 153rd National Meeting of the American Chemical Society, Miami Beach, Fla., April 1967. (2) We acknowledge with gratitude support for these studies from the National Science Foundation (GP 6738) and the National Institutes of Health (GM 05248). (3) (a) Taken in part from the Ph.D. Theses of H. M. Peters, Stanford University, Oct 1966, and D. M. Feigl, Stanford University, Oct 1965. (b) Parke, Davis & Co Fellow, 1965-1966. (4) H. S. Mosher, .I. E. Stevenot, and D. 0. Kimble, J . Amer. Chem. Soc., 78, 4374 (1956). (5) D. M. Feigl, Ph.D. Thesis, Stanford University, Oct 1965. (6) D. L. Dull, Ph.D. Thesis, Stanford University, June 1967. (7) B. J. G. McFarland, Ph.D. Thesis, Stanford University, Nov 1965. (8) J. S. Birtwistle, K. Lee, J. D. Morrison, W. A. Sanderson, and H. S. Mosher. J . Org. Chem., 29, 37 (1964), and references therein. (9) D. M. Feigl and H. S. Mosher, ibid., 88, 4242 (1968). (10) K. Freudenberg, "Stereochemie." Frans Deuticke, Leipzig, 1933, p 677.
known configuration. The results for the phenylalkylcarbinols are summarized in Table I, for the methylalkylcarbinols in Table 11, and for the t-butylalkylcarbinols in Table III.I1 The derivatives of (+)-phenyltrifluoromethylcarbinol exhibit rotational shifts comparable with those for the corresponding (+) -phenylalkylcarbinols if one excludes the acid phthalate of phenylmethylcarbinol from consideration. 1 2 9 1 3 It is not possible to make a logical arrangement of the data based upon the opposite assumption that (-)phenyltrifluoromethylcarbinol is related to the other (+)-phenylalkylcarbinols. Therefore, it seems reasonably certain, based upon these data, that (+)phenyltrifluoromethylcarbinol is configurationally related to the (+)-phenylalkylcarbinols as represented (11) These data are presented in modified form. Derivatives actually may have been prepared from either enantiomer, but the results reported in Tables 1-111 have been adjusted as if compounds of only one of the two enantiomers had been used. Enantiomerically impure samples were often uaed in the preparation of derivatives. However, great care was taken to prevent the concentration of either enantiomer during the synthesis o r purification of these derivatives, and the rotations presented in Tables 1-111 have been adjusted to those for enantiomerically pure derivatives using the known purity of the starting carbinols. (12) The rotation of the acid phthalate of phenylmethylcarbinol does not fit well into this series as has been observed earlier. At one time this anomaly rendered the assignment of relative configurations of the phenylalkylcarbinols uncertain. However, (+)-phenylmethyloarbinol and (+)-phenylethylcarbinol have been interrelated by direct chemical means18 and i t is now certain that they have t h e same relative configuration. (13) R. MacLeod, F. J. Welch, E. M. La Combe, and H. S. Mosher, J . Amer. Chem. Soc., 8 2 , 876 (1960).
~
4246 PETERS, FEIGL,AND MOSHER T.4BLE
The Journal of Organic Chemistry in Table I. Since the absolute configuration of (+)phenylmethylcarbinol (I) has been established unequivocally as R, (+)-phenyltrifluoromethylcarbinol (11) must have the absolute S configuration.
1
MAXIMUM MOLECULAR ROTATIONS 12 OF
HO-b-H
AND
DERIVATIVES"
CHa
Ph [MID," deg ---CarbinolBenzoate (neat) (neat)
R
Acid (in phthalate benzene) (in CHCla)
HO-C-H Acetate (neat)
Methyl $53 -45 $194 Ethyl -4lb8c +39 $100 $186 n-Propyl +44 $65 $130 $200 Isopropyl -98b3c $37 133 Cyclohexyl -95d +54 $178 $165 n-Butyl +28 $52 $200 $163 Isobutyl $40 $54 $110 &Butyl -240bse $45 +86 Trifluoromethyl -235 $56 $26 $69 $209 a Except for the trifluoromethyl compounds, all rotations were taken from R. MacLeod, F. J. Welch, and H. S. Mosher, J . Amer. Chem. SOC.,82, 876 (1960), unless otherwise noted. See ref 11 in text. b Compound prepared for the present study.6 Value given is for MD, not [MID. Specific rotation could not be calculated because density wm not available. d From M. P. Balfe, G. H. Beaven, and J. Kenyon, J. Chem. SOC.,1857 (1950). e Rotation taken in benzene.
+
TABLE I1 MAXIMUM MOLECULAR ROTATIONS CHI H-C-OH
OF
AND
DERIVATIVES"
R Carbinol (neat)
R
Acetate (neat)
[MID,"deg Benzoate (neat)
Acid phthalate (in CHCls)
+ +
Trifluoromethyl -6.3 +29 $0.3b 52 Ethyl $10.3c $30d $70' $88C,f Isopropyl $4.3 $25 $80 89 n-Prop yl $12.1 $22 $95 n-Butyl +12.0 $17 $117 &Butyl $7.8 $26 $93 $ 160 a Except for the trifluoromethyl compounds, all rotations are from P. G. Stevens, J. Amer. Chem. SOC.,55, 4237 (1933), unless otherwise noted. See ref 11 in text. * Value given is MD, not "[MID. Specific rotation could not be calculated because density was not available. C. E. Wood, J. E. Such, and F. Scarf, J . Chem. Soc., 1935 (1926). d R. H. Pickard and J. Kenyon, ibid., 105, 830 (1914). e J. Kenyon and R. H. Pickard, ibid., 107, 115 (1915). Rotation taken in ethanol.
TABLE I11 MAXIMUM MOLECULAR ROTATIONS R H ~ C - O H AND
OF
DERIVATIVES~
t-CaHs r
R
Carbinol (nest)
[MID," deg Acetate Benzoate (neat) (neat)
Acid phthalate (in CHCls)
+
Trifluoromethyl + 8 . 7 -50b $64* 148 Methyl $7.8 $26 93 160 - 14 $3.7 -0.5 0.0 Isopropyl - 39 - 44 Ethyl - 18 $3.3 n-Prop yl -20 $8.4 - 55 - 59 60 -51 -40 - 13 n-Butyl Isobutyl - 43 - 24 - 78 - 66 0. Except for the trifluoromethyl compounds, all rotations were taken from W. M. Foley, F. J. Welch, E. M. La Combe, and H. S. Mosher, J. Amer. Chem. Soc., 81, 2779 (1959). See ref 11 in text. * Value given i s for MD, not [MID. Specific rotation could not be calculated because density was not available.
+
-
+
Ph
R-(+) I
CFa HO-C-H Ph
8-(+ 1 I1
That (8)-phenyltrifluoromethylcarbinol (11) is configurationally related to (R)-phenylmethylcarbinol (I) results from the inversion in order of precedence assigned to the trifluoromethyl group and phenyl group compared with the other alkyl groups and phenyl according to the configurational nomenclature scheme of Cahn, Ingold, and Prelog. l 4 All the derivatives of both ( -)-methyltrifluoromethylcarbinol and (+ )-alkylmethylcarbinols have a positive rotational shift in progressing from the carbinols to the acetates, benzoates, and acid phthalates as represented in Table 11. Except for the benzoate, the magnitudes of the shifts for the trifluoromethyl compounds are comparable with those of the nonfluorinated derivatives. ,4lthough the benzoate rotation was close to zero, there is no reason to believe that preparation of the benzoate was accompanied by any racemization since the preparations of the other benzoates, including those of the other trifluoromethyl compounds, was not accompanied by racemization. Despite this one nonideal fit to the Freudenberg series, it is not logically possible to fit the (+) enantiomer of methyltrifluoromethylcarbinol and its derivatives to this series, and thus the evidence strongly supports the conclusion that ( - )-methyltrifluoromethylcarbinol is configurationally related to the other (+)-methylalkylcarbinols of Table 11. Since the absolute configuration of (+)-methylethylcarbinol (111), (+)-2-butanol, has been established as S with certainty,15 ( -)-methyltrifluoromethylcarbinol (IV) must have the absolute S configuration also. CFa HO-C-H
HO-C-H
The optical rotations of the esters of (+)-t-butyltrifluoromethylcarbinol are compared with those of other t-butylalkylcarbinols in Table 111. There is excellent correlation of increasing rotational shifts for these derivatives in going from the acetates to the benzoates to the acid phthalates with the exception of the isopropyl example which has already been discussed.le The correlations in going from the rotations of the neat carbinols to those of the acetate, however, are erratic. The rotational shift is slightly negative for the ethyl, n-propyl, and isobutyl compounds ; slightly positive for the methyl, isopropyl, and n-butyl compounds; but strongly negative for the trifluoromethyl case. Never(14) R. S. Cahn, C. K. Ingold, and V. Prelog, Angew. Chem. Intern. Ed. En&, 6, 385 (1966). (15) K.Wiberg, J . Amer. Chem. Soc., 74, 3891 (1952). (16) W. M. Foley, F. J. Welch, E. M. La Cornbe, and H. S.Mosher, ibzd., 81, 2779 (1959).
Vol. 33, No. 11, November 1968
CONFIGURATION OF SUBSTITUTED TRIFLUOROMETHYLCARBINOLS 4247
theless it is not possible to fit the enantiomeric (-)tbutyltrifluoromethylcarbinol and its derivatives logically into this series, and we are compelled to conclude that (+)-t-butyltrifluoromethylcarbinol is configurationally related to (+)-t-butylmethylcarbinol and the other (-)-t-butylalkylcarbinols of Table 111. It is reasonably certain that the absolute configuration of (+)-t-butylmethylcarbinol is 816l7* as represented by V and therefore the absolute configurations of the trifluoromethyl derivatives is R as represented in VI. CHa
CFs
H-C-OH
H-&OH
SCHEME Io
COOH
HO-C-H R
R
1. CHaOH,H*
2. 3.
R'I, Ag:O HlO,H
COOH R,o-C-H
R
R
11, (8)-(+), R = Ph IV, (8)-(-), R = CHs
The configurational designations for V and VI are S and
R, respectively, in spite of the fact that they are con-
IX, (8)-(+), R = Ph; R' = CHa XII, (AS)-(+),R = CHt; R' = CZHs 0 I n actual practice the (R)-(+) enantiomer of IV w&s employed, and it gave the ( R ) - ( - ) enantiomer of XII. However, it is represented here aa shown for the sake of clarity. The Experimental Section describes the actual isomer employed.
figurationally related. This is a result of the fact that in the Cahn-Ingold-Prelog rotational scheme t-butyl take precedence over methyl, but trifluoromethyl takes precedence over t-butyl. moderate yields. Furthermore it was determined that Although the results from the studies of rotational deuterium was not lost during the reaction from the shifts appeared to establish the absolute configuration a-deuterio derivative of 2-phenylbut,anoic acid, conof these three trifluoromethyl-substituted carbinols with firming that racemization did not occur by this pathreasonable certainty, several small points such as the way. Finally it has been found by Della23that sulfur anomalously low rotation of methyltrifluoromethyl tetrafluoride a t 70" converted cis- and trans-4-methylbenzoate and t-butyltrifluoromethyl acetate were not or 4-t-butyl-cyclohexanecarboxylicacids into the corcompletely satisfactory. Of primary concern was responding 1-trifluoromethyl-4-alkylcyclohexanewiththe fundamental assumption that a trifluoromethyl out isomerization, although at 130" isomerization did group would act normally as another alkyl group comoccur. parable with methyl or ethyl in a Freudenberg series. Thus there is ample precedence for the use of this reSince this was the first such study involving the applicaaction for correlations of configurations as shown in tion of Freudenberg's generalization to a series inScheme I starting with mandelic acid (VII) or lactic acid cluding the trifluoromethyl group, we felt that it should (X). Because the alcoholic hydroxyl group is conbe subjected to further verification. Furthermore verted into the fluoro group by this reagent, it was some of our asymmetric reduction results' were difficult necessary to propect it by conversion into the methyl or to rationalize with the absolute configuration found. ethyl ether. We therefore undertook a direct chemical correlation The preparation of (8)-(+)-0-methylmandelic acid which would be unequivocal. (VIII) has been reported.24 Upon treatment with sulfur tetrafluoride a t 30" for 2 days a 10% yield of the The method chosen is outlined in Scheme I. The key ~ reaction is the conversion of a carboxyl group into a tridesired trifluoromethyl derivative IX, [ a I z 6 +91.5' fluoromethyl group by the use of sulfur t e t r a f l u ~ r i d e . ~ ~(neat), * ~ ~ was obtained.26 (+)-Phenyltrifluoromethylcarbinol (11) , available from an asymmetric Grignard This method under mild conditions does not cause reduction14*5was converted into the same dextrorotaracemization. Martin and I
