DONALD J. CRAX,*ILBEKT LAXGELIANN -4311 FRED HAUCK
5750
I-01.
s1
The following control iri tetrahydroquinolitie was per(36.8 g.) was added and the mixture was stirred at room formed. Potassium metal, 0.193 g. (0.00484 mole), was temperature under nitrogen for 18 hours. The mixture was dissolved in 4 rnl. of tetrahydroquinoline and mixed with filtered under dry nitrogen, and 2-butanone (7.4 g.) was +12.1" ( 1 1dm., neat), and theresult0.617 g. of (+)-I, CPD added to the filtrate until the red color had just disappeared. ing mixture was refluxed for 24 hours. T h e product isolated The ether solution was washed with mater, dried, and the by the usual method contained olefin, T Z ~ D1.4889. This ether was removed. The residue was fractionally distilled t o material was rid of olefin by treatment with 2,4-dinitrogive 10 fractions. Fractions 1-5 contained some 2-butanone. ~ benzenesulfenyl chloride,15 and 0.30 g. of totally racemic I Fractions 6-9, 15.2 g., b.p. 75-77' (27 mm.), n Z 61.4876was obtained, ?Z%D 1.4879. 1.4878, was 2-phenylbutane (7475 yield). In a control run in N-methylaniline, the potassium was Anal. Calcd. for C10H14: C, 89.49; H , 10.51. Found: ~ CPDC, S9.60; H, 10.40. omitted. A solution of 0.35 g. of (+)-I, n Z 61.4878, $16.3' ( 1 1 dm., neat) and 6 ml. of dry N-methylaniline pot residue was crvstallized from pentane t o give 0.50 was heated t o 200" for 20 hours. T h e starting material was g. The white needles, m.p. 169-170". recovered in 77% yield, n% 1.4878, C?D +16.29" ( I 1 dm., Anal. Calcd. for C20H26: C, 90.16; H, 9.84. Found: C, neat). 90.15; H , 9.74. The structure of this compound was not Reaction of 2-Phenyl-2-butylpotassiumwith 2-Butanone. elucidated. -To 600 ml. of ether under dry nitrogen was added 16 ml. of sodium-potassium alloy. Methyl 2-phenylbutyl etherI3 Los . ~ G E L E S24, CALIF.
[CONTRIBUTION F R O X THE DEPARTMENT O F CHEMISTRY O F
THE
UNIVERSITY
OF
CALIFORXIA AT
LOS -%XGELES]
Electrophilic Substitution at Saturated Carbon. 11. Retention and Inversion Reaction Paths B Y DONALD J. C R A M ,
ALBERT LANGEMANN AND
FREDHAUCK
RECEIVED JASUARP 2, 1939 The effect of solvent on the stereochemistry of electrophilic substitution a t saturated carbon has been investigated. I n the base-catalyzed cleavage reactions of (-)-3,4-dimethy1-4-phenyl-3-hexanol,(-))-2,3-dimethyl-3-phenyl-2-pentanol, ( )-2,3-djphenyl-3-methyl-2-pentanol, (+)-3-methyl-3-phen~-l-2-pentanol and ( )-1,2-diphenyl-2-methyl-l-butanol, 2-phenJ-lbutane is produced as the result of solrent (as a n electropliile) donating a proton to negative carbon. Fourteen different solvents have been examined, and the optical purity of the 2-phenylbutane produced ranges from 96% (retention of configuration) t o Slyc (inversion of configuration). The steric courses of the reactions are relatively insensitive to variations in the leaving group, acidity and concentration of the nucleophile, and are controlled largely by the nature of the solvent. Solvents of low dielectric c r i s t a n t tend to give retention whereas solvents of high dielectric constant give inversion of configuration
+
+
In paper I of this series2 (which summarizes the relevant literature), eleven systems were subjected to base-catalyzed (anionic) cleavage reactions in secondary amines as solvents to give 2phenylbutane as product. The reaction was found to occur in each case with predominant retention of configuration a t C-2 of 2-phenylbutane. CH3
*I Ir: C?HjC-C--1 41-
I
+ H-h-
Qv
I
---+ *I
C2HsC-H
of diastereomers6 configurationally homogeneous a t the carbon atom which undergoes substitution. The 2-phenylbutane (I) produced was characterized by its refractive index in all cases, which constant is very sensitive t o olefinic and other contaminants, and serves as a good criterion of purity. In representative cases, the infrared spectrum of this hydrocarbon was also compared with that of authentic I,' and in all cases the spectra were superimpossible. In a number of reactions carried out in tertiary alcohols or ethers as solvents, mixtures of
-+ C=l' + g-
C6H5
I
The present paper reports the results of a survey of sixteen solvents to assess their effect on the steric course of the cleavage of five systems of the type formulated. The relative configuration of starting materials and products have been established elsewhere.3s4 Results Table 115records the conditions for and the results of cleavages of system I X , which is a mixture (1) T h i s work was sponsored by the Office of Ordnance Research, U. S. Army. (2) D. J. Cram, .4. Langemann, J. Allinger and K. R. Ropecky, THISJOURXAL, 81, 5740 (1959). (3) D. J. Cram and J. Allinger, ibid., 76, 4516 (1954). (4) D. J. Cram, K. R. Kopecky, F. Hauck and A. L a w e m a n u , ibid., 81, 5754 (1959). ( 5 ) Tables, compounds and runs are numbered consecutively throughout t h e first six papers of this series
CHB (- )-IS
n,b-UnSatUrated ketones (cimdensation products)
t-
a,P-unsaturated ketones were isolated which are presumably condensation products of 2-butanone produced in the cleavage reaction. In some of the runs in primary and secondary alcohols, these a,P(6) D. J. C r a m and J. D. Knight, Tms J O U R N A L , 74, 5835 (1952) ( 7 ) D. J. Cram, ibid., 74, 2149 (1952).
Nov. 5, 1959
RETENTION AND INVERSION REACTION PATHS
- -
d 8
Y
U U
3 U
Y 9
b
5751
5752
DOXALD J. CRAM,ALBERTLANGEMANN AND FRED HAUCK
VOl. 81
unsaturated ketones appeared to have been re- oxide is undoubtedly undergoing fragmentation, duced to their corresponding alcohols. and the general mechanistic class can be defined by Attempts were made to cleave (-)-IX in water, the expression formulated. Thus the reaction nitrobenzene and formamide, but starting material whose stereochemistry is under observation is that was recovered unchanged in each case. The insolu- of electrophilic substitution a t saturated carbon. bility of I X in water accounts for its failure to cleave, whereas in the other two cases the base was a (614 a 0 destroyed by solvent faster than cleavage occurred. \* I r* Solvent \* I/ b-C-C-d H-B -+ b-C-H C-d Alcohols (-)-X, (+)-VIII, (+)-VI1 and (+)-VI I /- 1 / were all prepared from optically pure 2-methyl-2C e C e GG phenylbutanoic acid by procedures that have U L 2 I been previously r e p ~ r t e d . ~ These systems were Seat of Leaving Electrosubsti- group phile cleaved in enough solvents to determine whether they were similar in their behavior to I X , which tution was examined more thoroughly. The results are Correlation between Stereochemical Outcome of recorded in Table 111. Electrophilic Substitution and the Dielectric ConControl experiments (see Experimental) estab- stant of the Solvent.-The results of Table I1 indilished that 2-phenylbutane (I) is optically stable cate that the solvent-electrophile plays a dominant under the conditions of most of these experiments. role in controlling the stereochemistry of the An exception is run 23 (Table 11). I n a control electrophilic substitution reaction. In the cleavexperiment, optically active I racemized 4% under age of I X in 14 different solvents, the stereospecithe conditions of run 23. System (-)-X failed $city of the reaction ranges from 93y0predominating to cleave in tri-n-butylamine and di-n-amylamine retention to 51 % predominating inversion of conjigua t temperatures of 225 and 210”, respectively. Ap- ration. These results demonstrate that a t least two parently these bases are not strong enough to cause mechanisms are operative; one which occurs with reaction. retention and one with inversion of configuration. A third mechanism, one which is stereochemically P- + indiscriminate and leads to racemic product, might also be involved. I n no single reaction was a single mechanistic path followed. The task a t hand is to identify and describe these mechanisms, and to correlate the structural and environmental factors Potassium salt of ( - )-S which control them. In this paper a preliminary Ketone condensation products correlation of this sort will be made, but detailed discussions of mechanism are reserved for pailc pers Vgaand VIgbof this series. The solvents employed for cleavage of IX (Table 11) differ from one another in many respects. They vary in basicity, acidity, in dielectric constant, in their ionizing and dissociating power, and in the number of proton-donating groups which they Potassium salt of (+)-VI11 CH3COCeH5 contain per unit volume of solvent. Of these properties, the dielectric constant (which to a limited extent also provides a measure of ionizing and +dissociating power) correlates best with the stereoI + KB chemical results. This fact is illustrated by the data of Table IV. This correlation is by necessity crude, since the dielectric constants change with Aldehyde condensation Potassium salt of (+)-VI1 temperature, and the reactions whose results are products quoted in Table IV were not run a t the same temperature. Nevertheless, when the values of kret/ r\- + kinv are arranged in decreasing order, this order is almost the same as the order of increasing dielectric constant. The expression of the stereochemical result in terms of kret/kinV allows a continuous scale to be constructed which permits the relative rates Aldehyde condensation of the two stereospecific processes to be compared, a t Potassium salt of (+)-VI and disproportion least in a primitive sense. The values of k r e t l k i n v products vary by a factor of 84, while the values of the dielectric constant ( E ) vary between 2 and 46. Discussion The existence of this correlation suggests that Evidence is provided in a later papera of this se- some undissociated species such as A gives rise to ries that homolytic does not compete with heteroly- product with predominantly retained configuration, tic cleavage in systems VI-X. Since these reac-
+
+
+
+
+
+
+
tions are base catalyzed, a species such as an alk(8) D. J Cram, A. Langemann, W. Lwowski and K. R . Kopecky, THISJOURNAL. 81, 5700 (1959)
(9) (a) D. J. Cram, F. Hauck. K. R. Kopecky and W. D. Nielsen, ibid., 81, 5787 (1969); (b) D. J. Cram, J . L. Mateos, F. Hauck, H. Langemann, K. R. Kopecky. W D. Nielsen and J. Allinger, ibrd., 81, 5774 (1959).
Nov. 5, 1959
RETENTION AND INVERSION REACTION PATHS
TABLE IV CORRELATIONBETWEEN STEREOCHEMICAL COURSE OF CLEAVAGE REACTIONS O F ( - )-3,4-DIMETHYL&PHENYL-3HEXANOL ((-)-IX) A N D DIELECTRIC CONSTANTOF THE SOLVENT SYSTEM Normality of electrophiles in “C. medium
kret/
Run“
kev
Solvent
28 2% 16 CeHe 17 620 llb C H ~ N H C ~ H B 17 1119 18 (CHs)sCOH lgm 19 CHaCHOHCzHa 12 6 18% 20 CHI( CHZ)SOH 4 27% 21 CzHbOH 1618 23 HzNCH2CHzFHz 1.5 1.2 3418 24 CHsOH 35% 27 O(CHzCH20H)z 0.56 3Sz0 30 HOCHzCHpOH 0.35 0.33 46% 32 HOCH2CHOHCHgOH See Table I1 for experimental details. Table I, I of this series.
1
9 13 13 13 22 66 31 18 32 33 paper
while a partially or wholly dissociated species such as B forms product with a predominantly inverted configuration. The equilibrium constant, K , would be very sensitive to the dissociating power of the solvent, which in turn correlates with the dielectric constant. H-B
. .
a
\* /
O h
b-C-C-d
1
I
C
e
A
a
\*
b-C-H
/ C’
Predominantly retained configuration
a
\* /
0 . . .H-B..
I
\*
+
.M
-C-d b-C-C-d C
I
e B
a
*/ H-C-b \ C
Predominantly inverted configuration
Since the reaction of either A or B involves a proton donor (H-B), the question arises as to whether there is any correlation between the concentration of proton-donating functional groups in the solvents of Table IV, and the ratios of k r e t l k i n v . I n the last column of this table, the normalities of the proton-donating functional groups of the media are listed. Except for ethylenediamine, which is a very weak acid, there exists a crude correlation between the values of k r e t / k i n v , and the concentration of electrophiles in the medium. The inversion mechanism appears to be favored by a high concentration of H-B, whereas the retention mechanism dominates in media with a low concentration of H-B. Most of the solvents which give inversion contain the bifunctional units -0CH2CHzOH. This structural feature undoubtedly enhances the dissociating power of the solvent toward metal salts, since two coordination sites are available to metal cations on
5753
each solvent molecule. That such a structural feature is not controlling is shown by the results of runs 22, 36, 37 and 46, in which the electrophile contained this part structure, and yet the reactions went with from 7 to 60% predominant retention of configuration. That inversion of configuration can occur in a solvent without this structure unit is demonstrated by run 42 conducted in methanol. The reaction occurred with 4270 predominating inversion. Effect of Leaving Group on the Steric Course of Electrophilic Substitution.-Although much less data were obtained for systems VI, VII, VI11 and X than for IX, the results of Table I11 indicate that the steric course of the reactions of all five systems shows the same kind of sensitivity to medium effects. System X cleaved in various solvents to give values of k r e t / k l n v that varied between 38 and 0.28, or by a factor of 135. System VI11 gave values that range between 17 and 0.23 (factor of 74), whereas the values obtained for the two cleavages of VI1 that have been reported thus far (runs 8 and 44) are 3 and 0.56. For VI, the extreme values of kret/’kinv are 10 and 0.33 (factor of 33). Although the nature of the leaving groups of these systems was different enough to make the reactivities of the substances vary a great deal, all of the systems show the same sort of sensitivity toward the medium with respect to the stereochemical course of their reactions. If with each of the five alcohols, the runs are arranged in order of decreasing values of kret/’kinv, the order of solvents which results is the same for each starting material. Systems that contain an even wider range of types of leaving groups cleave to give product with predominating retention of configuration in Nmethylaniline, although the stereospecificity of the reactions could not be accurately measured2 in many of the systems. The correlations between the steric course of these reactions and the nature of the solvent are visible in spite of the fact that the other conditions for the runs were far from constant. The temperatures ranged from 72 to 237’, the concentrations of the starting materials varied from 0.1 to 2 molar, the concentrations of the basic catalyst varied from 0.1 to 2 molar, and the pKa’sof the electrophile varied from 16 to an estimated 30.1° Although these variables play some role in controlling the stereochemical course of the electrophilic substitution reaction, the present data indicate that medium effects dominate. Experimental Purificdion of Solvents.-All solvents used in the clea.vage reactions were purified through distillation from sodium metal or the alkoxide formed from sodium and the alcohol. The pentane employed for extraction and chromatography was distilled through a 50-plate (bubble) column, and was free of olefin. Dioxane was purified by the method of Fieser .I1 Cleavage Reactions.-In the cleavage reactions, the reaction solvent was first saturated with dry nitrogen. The metal was freshly cut under clean mineral oil, cleaned and weighed under dry pentane. The metal was added to the (10) This value is estimated for the p K . of N-methylaniline from t h e table of pK. values for various substances listed by W. K. McEwen, THIS JOURNAL, 68, 1124 (1936). (11) L. Fieser, “Experiments in Organic Chemistry,” D. C. Heath and Co., Boston, Mass., 1941, p. 369.
5754
D. J. CRAM,K. R. KOPECKY, FREDHAUCK AND ALBERTLANGEMANN
reaction solvent under nitrogen, arid dissolvcd with the aid of heat where necessary. lt'hen potassium was dissolved in diethylene glycol, the mixture had t o be swirled to prevent local heating. Potassium could not be dissolved directly in ethylene glycol without explosion. Dry potassium t-butoxide was f i s t prepared, added to ethylene glycol, and the t-butyl alcohol was distilled from the mixture along with some of the ethylene glycol. When potassium was dissolved in methanol or ethanol, the mixtures were cooled with Dry Ice to control the reactions. The reactions carried out below or a t the boiling point of the reaction medium were run in open systems under a nitrogen atmosphere. Runs made above the boiling points c l f the medium and a t 150" or below were carried out in heavy-walled pressure bottles (100-ml. capacity). Above this temperature, heavy-walled sealed tubes were used. Lt'ood metal-baths heated electrically were employed. The isolation procedure is illustrated as follows: Run 37.-In 10 ml. of nitrogen-saturated monomethyl ether of ethylene glycol was dissolved 0.254 g. (6.50 mmoles) of freshly cut oil-free potassium. When solution was complete, 1.OS7 g. (5.64 mmoles) of ( - )-2,3-dimethyl-3-phenyl2-pentan01 was added in enough additional solvent t o give a total volume of 55 ml. T h e mixture was maintained in a bath a t 202' for 24 hours under a slight nitrogen pressure acting through a spiral condenser. T h e mixture was cooled, diluted with 2 volumes of water, and extracted 3 times with pentane. T h e combined extracts were washed 3 times with water, dried, evaporated t o a small volume through a twofoot Vigreux column, and the residue was adsorbed on 70 g. of activity I alumina.12 T h e desired product (2-phenylbutane) was eluted with pentane, and the solvent was evaporated through a two-foot Vigreux column t o an oil. This material was twice distilled through a micro-Claisen still a t 40 mm. pressure t o give 0.628 g. (83%) of 2-phenylbutane, n2% 1.4875, @D +3.93" ( I 1 dm., neat). This material possessed a n infrared spectrum superimposable on that of authentic 2-phenylbutane. The product of runs 16, 18, 19, 20 and 33 also possessed infrared spectra identical to that of authentic 2-phenylbu(12) H. Brockmann and H. Schodder, Ber., 74B,73 (1941).
[CONTRIBUTION FROM THE
DEPARTMENT OF
Vol. 81
t m e . From tlie chroinatogram of the product from run 16 wds eluted with ether a colorless liquid (0.316 g. from 1.0 g. of starting [(-)-IX], @D -7.17 (1 1 dm., neat)). T h e infrared spectrum of this material showed the presence of starting material and ketones (1650 cm.-' in infrared and Amax 212 mp in ultraviolet spectra). When treated with 2,4dinitrophenylhydrazine in ethanol and hydrochloric acid, 30 mg. of a red derivative was isolated, m.p. 125-129'. This material was not characterized further, but seemed t o be a mixture of derivatives of unsaturated ketones (infrared and ultraviolet spectra). Optically pure starting material was isolated from runs 31, 32, 33, 38 and 49. Acetophenone, characterized as its 2,4dinitrophenylhydrazone, was isolated from run 40. Control Runs.--As a control on runs which involved potassium glycoxide as base and 2-phenylbutane as product, the following run was made. A 1 M solution of potassium diethylene glycoxide in diethylene glycol was prepared, and 50 ml. of this solution was refluxed a t 244' for 24 hours ~ a Z 6~12.4" with 0.300 g. of 2-phenylbutane, n Z 51.4878, ( I 1 dm , neat). Starting material (0.210 g.) was recovered (1 1 dm., in the usual way, n% 1.4876, @D -12.4' neat). As a control for those runs in which potassium t-butoxide was employed and 2-phenylbutane was product, the following experiment was carried out. To a 0.8 molar solution of potassium t-butoxide in t-butyl alcohol (10 ml.) was added 0.35 g. of 2-phenylbutane, n Z 5 D 1.4878, 0 1 % ~ +16.30" (1 1 dm., neat) The solution was sealed in a heavy-walled tube and heated to 200" for 20 hours. Recovery of 2-phenylbutane in the usual way gave 0.25 g. of material, n% 1.4878, CY% f15.49' (1 1 dm., neat). In this treatment, 2-phenylbutane was 5% racemized. All of the runs of Table I that involve potassium t-butoxide as base were run a t temperatures of 150' or less, and a t lower base concentrations. As a control for run 23, under the condition of the experiment, optically active 2-phenylbutane was found t o racemize 4%. 9procedure similar to those reported above was employed. LOS -1NGELE.S
24,
C.41,IF.
CHEMISTRY O F THE UNIVERSITY OF CALIFORXIA AT LOS h G E L E S ]
Electrophilic Substitution at Saturated Carbon. 111. Effect of Solvent Composition on Reaction Path1 BY DONALD J. CRAM,KARLR. KOPECKY, FREDHAUCK AND ALBERT LANGEMANN RECEIVED JANUARY 2, 1939 The stereochemistry of the base-catalyzed cleavage reactions of three tertiary alcohols (VIII, I X and XIV) and two ketones (V and XV) have been studied. In dioxane with about 5% diethylene or ethylene glycol a s a proton source (electrophile), the three alcohols cleave t o give electrophilic substitution at saturated carbon which occurs with from 69 to 9570 ?redominating retention of configuration. In diethylene glycol, these alcohols cleave with from 41 to 5870 predominating inverszon. In all three systems, as the amount of glycol in dioxane is increased, the steric course undergoes a smooth transition from predominant retention to predominant inversion of configuration, In cleavages of the three tertiary alcohols in dioxane with 1% t-butyl alcohol as the proton source, electrophilic substitution occurs with from 84 to 96% predominating retention of configuration. Ketones V and XV cleave in dioxane with 1% t-butyl alcohol as proton source with 74 and 6170 predominating retention, respectively, and in diethylene glycol with 38 and 17% predominating inversion, respectively. The stereospecificity of the reactions of X I V in dioxane and of VI11 in diethylene glycol were found t o decrease with increasin5 temperature. I n the intermediate solvent, methanol, alcohol I X gave product with 25yo predoniinating inversion a t 180 , and with 9yopredominating inversion a t 210'.
The previous papers2 in this series report the results of a survey of cleavage reactions and of solvent-electrophile systems suitable for determining the stereochemistry and mechanism of electrophilic substitution a t saturated carbon. Eleven compounds which correspond to the general structure formulated (the leaving group, C-Y, was varied) (1) This work was sponsored by the Office of Ordnance Research, U. S. Army. ( 2 ) (a) D. J. Cram, A . Langemann, J. Allinger and K. R. Kopecky, THISJ O U R N A L , 81, 5740 (1959); (b) D. J. Cram, A. Langemann and F Hauck, i b i d . , 81, 5750 (1959).
were found to cleave to give 2-phenylbutane (I). The steric courses of the reactions were found to correlate with the dielectric constants and with the concentration of proton donors in the medium.
