OPTICAL ACTIVITY AND CHEMICAL STRUCTURE* - The Journal of

[CONTRIBUTION FROM

LABORATORIES OF THEROCKEFELLER INSTITUTEFOR MEDICAL RESEARCH, N. Y.]

THE

OPTICAL ACTIVITY AND CHEMICAL STRUCTURE* P. A. LEVENE

AND

ALEXANDRE ROTHEN

Received March 9, 1936 I. HYDROCARBONS

A. Normal Series. B. Hydrocarbons containing an isopropyl group. C. Hydrocarbons containing a phenyl or cyclohexyl group. 1. Phenyl and cyclohexyl series. 2. Benzyl series. 3. Methylphenethyl series. 11. CARBINOLS

A. Secondary carbinols of normal series. B. Primary carbinols of normal series. C. Carbinols of isopropyl and isobutyl series. D. Carbinols containing an ethylenic group. E. Secondary carbinols containing a phenyl or cyclohexyl group. 1. Phenyl series. 2. Cyclohexyl series. 3. Benzyl series. 4. Phenethyl series. F. Primary carbinols containing a phenyl group. 111. ACIDS, NITRILES, AND ALDEHYDES

A. Carboxylic acids of the normal series. B. Carboxylic acids having a phenyl or a cyclohexyl group. C. Normal aliphatic nitriles. D. Aliphatic aldehydes. E. General discussion of observations on substances of the type

F. A test of the correctness of the configurational relationships assigned to substances discussed in this section. IV. APPLICATION OF THE RESULTS RECORDED I N THE PRECEDING SECTION

A. Absolute configurations B. Secondary and primary C. Secondary and primary D. Secondary and primary

of secondary and primary carbinols. aliphatic amines. aliphatic azides. aliphatic halides.

* The present summary was prepared a t the request of the Editors. 76

OPTICAL ACTIVITY AND STRUCTURE

77

Given a substance of known configuration of the general type of formula I, CH,

I I (CH2)7&* I

H.* C **(CHZ),,X R3

I (where X = a functional group; R3 = an alkyl or an aryl radical; n2 and n3 = 0 or an integer), the configuration of the derivative obtained by substitution of X by Y cannot be predicted when n2 = 0, whereas when n2 = an integer the substitution cannot produce any change in the original configuration. Similarly, when R3 is substituted by R:, it is possible to predict the configuration of the derivative only when n3 = an integer and not in the case when 723 = 0. The question arises: Is it possible to predict the configurations of the substitution-derivatives in the cases when Q = 0 or n3 = 0, on the basis of observations on the derivatives when n2 or n3 are integers?? The first requisite for the solution of the problem was to render available series homologous with respect to nz and n3 in which the configurations of all members had been established by methods of classical organic chemistry. When such homologous series were prepared, it was observed that, frequently, members of the same series differed in the direction of their rotation. This phenomenon naturaIly required an explanation. The modiern theory of optical rotation postulates that the optical rotation (even of the simplest organic molecule of the type

R1 I H..kJ. .&,

I

R8 having only one asymmetric center) is the sum of the partial rotations of each of the four substituents, there being an equal number of dextrorotatory and levorotatory partial rotations.’ Thus, when two members of a homologous series differed in the sign of their rotation, it was evident

t The present article will summarize work of this laboratory on only one phase of the problem; other work of the laboratory dealing with the problem of the relationship of chemical structure to optical activity will be discussed a t a future date. 1 KUHN,W., in FREUDENBERG, “Stereochemie,” Franz Deuticke, Berlin and Wien, 1932, p. 317.

78

P. A. LEVENE AND ALEXANDRE ROTHEN

that this difference could be caused either by an inversion in sign of the rotation of one or more of the partial rotations, or by change in the numerical values of one or more of the partial rotations. Hence, for the solution of this problem, information was required as to the partial rotations of the chromophoric groups of each substituent. The analysis of rotatory dispersion curves extending to the region of the absorption bands (or the greatest proximity to it) offers a method for the solution of the latter problem. Thus the work naturally falls into two parts: one aiming at the building up of homologous series and the other concerned with the direction and relative values of the partial rotations of the significant chromophoric groups. I. HYDROCARBONS

The simplest group of optically active organic molecules obviously are the trisubstituted methanes of the type

CH3

I I

H ** C -.(CH2)n2Rz (CHz)naCH3 (Rz = CH3, isopropyl, phenyl or cyclohexyl group).

A . Normal Series Of these hydrocarbons the simplest are those in which Rz = CH3. The building up of a single homologous series of normal hydrocarbons is a comparatively simple task since any number of homologous members may be prepared from a single parent substance under conditions excluding the possibility of Walden Inversion. Thus, starting from a disubstituted acetic acid, it is possible to synthesize all the members of a homologous series by the following set of reactions:

CH,

I

Ha . C . -COOH+

I

(CH2)naCH3 I

CH3

CH3

CH3

I I I H . . C - .CHzOH + He .C. -CH2Br + Ha . C . .CH3 I I I (CH2)n8CH3 I1

(CH2),,CHB IV

(CHJnaCH3 I11

L CH3

. . . . continue as in case

II+III+IV.


79

It will be seen later that it is possible to correlate the acids where 122 = 0 with. those where n2 = 1, 2, 3 or any higher integer, by methods of classical organic chemistry. Likewise, it is possible to correlate by the same methods, acids varying with respect to 723. Hence it is possible to build up any desired number of homologous series of hydrocarbons of known configuration. Table I summarizes the results of the observations. It if3 evident from Table I that the direction of rotation of the substances of this group depends entirely on clockwise or counter-clockwise arrangement of the substituents. Dextrorotation is assigned to the members in TABLE I CONFIGURATIONALLY RELATEDNORMAL HYDROCARBONS [MI: Max. (Homogeneous)

I

which the groups are arranged in clockwise order (according to descending volumes) when viewed with the largest volume towards the observer-in harmony with the considerations of Boys.2 Tlne analysis of rotatory dispersion curves of these substances indicates the possibility that the rotation in the visible can be expressed by the sum of two contributions of opposite sign, i.e., by a Drude formula of two terms with1 opposite signsn3 *?BOYS, S. F., PTOC. Roy. Soc., Al4.4, 655 (1934). :LEVENE, P.A., AND ROTHEN,ALEXANDRE (unpublished results).

a

80


B. Hydrocarbons Containing an Isopropyl Group In this group of substances -CH

CH3

stands for Rz and n2 = 0 , l or 2. 2 have not yet been prepared) reveals a periodicity in the shift of rotation of successive (with respect to nz) members. Thus, from isopropyl to isobutyl the shift is to the left, whereas from isobutyl to isoamyl the shift is to the right. (4). The maximum rotation of the methylamylisoamylmethane (member in the last column and the last row) is 0.2", thus showing that a t the distance (CH& from the asymmetric carbon atom the partial contribution of the isopropyl group is nearly equivalent to that of the normal propyl group. It might be expected that the configurationally related methylhexylisoamylmethane would rotate in opposite direction from that of the members of the last column given in Table 11.

C. Hydrocarbons Containing a Phenyl or a CycEohexyl Group

CH3

I I

H ** C **(CHZ),,CHs (eH~)nt

I

R3

(Rp = phenyl or cyclohexyl group). 1. Phenyl and Cyclohexyl Series.-The

rotations of the individual members of the two homologous series have been established by their origin from members of a homologous series of acids.6 The relationship of the phenyl t,o the cyclohexyl series follows from the conversion of the former through catalytic hydrogenation to the latter. The correlation of the configurations of the phenyl to the normal hexyl 5

6

LEVENE,P. A., AND ROTHEN,ALEXANDRE (unpublished results). LEVENE,P. A., AND MARKER, R. E., J . B i d . Chem., 93,749 (1931);97,563 (1932).

83


series is based on preparation of the members of the two series from the same disubstituted acetic acids of known configuration by the following set of reactions:' CH3 OH

I I

I I

Ha . C . * . C . C H ~ . C H ~ . C H Z . C H = C H (60 ~ %) CZH5 H

/

CH, 0

I

/I

/

I . .C - .C .0C2H6+ BrMg(CHJ5MgBr

CH3 OH CHZ-CHZ

I

H .C

-+

I

I

CzH6

CzHs dextro

L

CH3

CH3

I T * C *CZ€& I *

- . .CI /

*

I

I

C6H13

CZH5

levo

dextro

\

CH2-CH2

I

CH3

H * * C* *CeH13

\

CHz-CHz

I

/ Ha * C .*CH \

\

&zH~ CHZ-CHZ

/

/CHz

CH3 CHZ+H. * C **C6H5

levo

CZH5 dextro

2. 13enzyl Series.-The configurational relationship of methylethylbenzylmethane to methylethylheptylmethane is based on the preparation of the two substances from the identical 2-methylbutyl butanal-1.8 CH3

0

I / / H . C . .C-H I

CHs

+ GHIMgBr+

H.

.A.I

.CH(OH)C&

C2H6

CZH5 [MI: := 6.25

+

[MI:

=

- 0.54

CH3 H . * C *.CHz,Ce,Hrj

I

CZH5

[MI: 7 8

=

(40

+ 1.85

LEVENE,P. A., AND HARRIS, STANTON A , , ibid., 111, 725 (1935). LEVENE,P. A., ibid., 110, 323 (1935).

HI -k Hz+

%)

84


C2HS dextro

c2HS

dextro

3. Methylphenethyl Series.-Configurational relationship of methylethylphenethylmethane to methylethyloctylmethane is based on the synthesis of the two hydrocarbons from two 2-methyl-1-bromobutanesDof identical configuration as follows : CH3 CH, I I H.-C.-CH2Br + H..C..CH2MgBr

I C2H6 [MI: = + 1.49

I

0

\\

+

H

C2H6

CH,

C-CeH6_,

/-

CH3

I

H ** C .*CH~CH(OH)CGHS I I

Hz+ H

-

A-

CH2CH2C6H6

I I

C2H6 [MI: = $6.62

C2H6 [MI: = $5.09 CH3

0

&Hs [MI: = +6.6 9 KLAGES, A., AND SAUTTER, R., Ber., 37, 649 (1904). LEYENE,P. A., AND HARRIS,STANTON A,, J . Biol. Chem., 111, 735 (1935).


85

The maximum rotations of the three “phenyl,” “cyclohexyl” and “normal aliphatic” hydrocarbons have been calculated on the basis of the maximum rotation of the parent substances and the results are summarized in Table 111. TABLE I11 CONI~IGURATIONALLY RELATED HYDROCARBONS OF THE NORMAL, CYCLOHEXYL AND PHENYLSERIES [MI: Max. (Homogeneous)

From Table I11 it may be seen that in the case of the cyclohexyl derivatives of the general type

CH3

I 1

H *. C *.CZHs (CH~)~,CBHII with increase in the value of n3 from 0 to 1 and 2, the events parallel those in the case of the isopropyl series, namely, there is observed a change of sign of rotation when n3 (nz in the “iso” series) changes from 0 to 1 and there is a shift in direction of the rotation in the opposite sense when the value of n3 (nz in the ‘‘iso” series) changes from 1 to 2. In a later section of this article other evidence will be presented pointing to the similarity of the cyclohexyl group to the isopropyl group as regards their influence on o:ptical activity. However, the two groups differ with respect to the value of na (nz in the “iso” series) at which their effect on optical rotation ceases to have an influence other than that of the corresponding normal alkyl group. It was stated earlier that the maximum rotation of methyl-

86


amylisoamylmethane (in which the isopropyl group is at a distance (CH2)2 from the asymmetric center) approaches a zero value whereas the cyclohexyl group at the same distance produces a marked effect on optical rotation as seen from the maximum rotation of methyloctylhexahydrophenethylmethane.1O

CH3

I I

He * C **CaH17 (CH2)2CsHn [MI:

M ~ =~ -5.27 .

In the light of these observations the a priori statement of W. Kuhn10e5 to the effect that the rotatory contribution of a cyclohexyl group is equivalent to that of a normal hexyl group should be rejected. In the case of the “phenyl” derivatives of the type

CH1

I

Ha * C *.C2H,

I

(CHz),,CsHci there is likewise observed a periodicity in the shift of rotation with the changes of the values of 123 from 0 to 1 and from 1to 2. No change in the direction of rotation occurs on passing from the value of n3 = 0 to n3 = 1. Analysis of the rotatory dispersion curve of methylethylphenylmethane, however, revealed the fact that the rotatory dispersion of this substance is anomalous, thus showing that the partial rotation of the nearest active absorption region of the phenyl group is of opposite sign from that of the rotation of the hydrocarbon in the visible region, whereas in the case of the benzyl and phenethyl derivatives, the dispersion curves are normal,l’ indicating that the course of events on change of the value of n3from 0 to 1 is similar in the cases of the phenyl derivatives and the cyclohexyl derivatives. 11. CARBINOLS

A . Secondary Carbinols of the Normal Series CH,

I

H . * C *.OH ii.3

LEVENE,P. A., AND HARRIS,STANTON A., J . Biol. Chem., 111, 735 (1935). 10.6 KUHN,W., Z. physik. Chem., B31, 23 (1935). 11 LEVENE,P. A., AND ROTHEN, ALEXANDRE (unpublished results). 10

87


The configuration of these substances has been correlated with that of lactic mid. Three methods have been employed to that end. 1. The first method consists in reducing a-hydroxyacids to the corresponding glycols and converting the glycols into secondary carbinols. Thus t,he configuration of the simplest carbinol of this series, 2-hydroxybutane1 can be arrived a t by the following set of reactions:12

CH3

CH3

CH,

COOH

COOCZH6

I I H . * C * * O -+ H H * * C * * O H-+ H . . C * . O H-+ I I I dextro

CHzOH

levo

CH3

CH3

I

He * C -.OH

I

-+

CHz

dextro

I Ha . C - *OH I

CHI +

CH2

I

I

CHzOH

CHzI

dextro

I I CHz I

H . * C **OH

dextro

CH3

dextro

2. The second method is illustrated by the case of ethylpropylcarbinol. Taking for granted that the configuration of 3-hydroxyvaleric acid is known (it is readily determined by methods of classical organic chemistry), the configuration of the carbinol can be arrived a t by the following set of reactions :13

CzHs

I H . . C . .OH I

CHzCOOH dextro

CzHs

I

01 Ha . C - .OH

I

CHzCH=CHZ dextro

CzHs

I

H . . C . .OH

I

CHZCH~CH~ dextro

3. A third general method is exemplified by condensation of propylene oxide (or any other ethylenic oxide) with a Grignard reagent. This method became available only after the configuration of the lower members o:! the homologous series of optically active carbinols had been establ2

LICVENE, P. A., AND HALLER,H. L., J . Biol. Chem., 66,49 (1925); 67, 329 (1926);

69, 165 (1926); 74, 343 (1927); 76, 415 (1928); 77, 555 (1928). LEVENE,P. A,, WALTI,A., AND HALLER, H. L., ibid., 71, 465 (1927).

LEVENE,P. A., HALLER,H. L., AND WALTI,A., ibid., 73, 591 (1927). 13 LICVENE, P. A., AND HALLER,H. L., ibid., 79, 475 (1928); 81, 425 (1929).

88


lished by the methods described in (1) and (2). It was then possible to establish the fact that the reaction proceeds without Walden in~ersi0n.l~

0

CH3CH(OH)COOH

-+

/\

CH,CH(OH)CH20H + CH3.CH .CH2

levo

dextro

levo RMgBr

>

CH3CH(OH)CH2.R levo

Table IV contains a summary of the results of observations on the secondary carbinols of the general type

R1

H.

-A.

.OH

(n3 = 0 or an integer; R1 = an aliphatic radical). From Table IV it may be seen that the direction of rotation, in the members of this group of substances, seems to be determined by the position of the radical with the longest carbon chain. Prior to the publication of the work of our laboratory, the question, as to whether or not all members of the ethyl and the propyl series (and series with still higher homologues of R1)should be of the same sign, was debated.15 From Table IV it may be seen that in each of these series the rotations of the individual members pass a zero value and then change their direction. Thus it is evident that if it were desired to separate the secondary carbinols into a d and 1 series, the dividing line of the two series would be that joining the symmetric carbinols. The series above this line should belong to the 1 series and those below to the d series. In other words, each new series should begin with a symmetric member. For practical purposes it is often advantageous to begin each new series with a member having R1 = CH3.

B. Primary Carbinols of the Normal Series

CH3

I I

H * * C * * (CHI),,OH (CHz),,CH, LEVENE,P. A., AND WALTI,A., i b i d . , 71, 461 (1927). KENYON,J., J . Chem. SOC.,106, 2226 (1914). CLOUGH,G . W., Proc. Chem. SOC.,2B, 357 (1913). l4 16


89

Comparatively few optically active primary carbinols of this type had been known prior to the work of our laboratory. The configurations of these carbinols cannot be correlated by methods of classical organic chemistry with those of the corresponding secondary carbinols (those

TABLE IV CONFIQURATIONALLY RELATEDNORMALSECONDARY CARBINOLS. [MI: Max. (Homogeneous)

I

I

having n2 = 0). However, they can be correlated by such methods between themselves and to the acids of the general type CHs

I I

Ha * C **(CH2),,COOH 333

(where nz = 0 or an integer, Rs = normal aliphatic radical).

90


From the latter they are prepared by reduction of the corresponding ethyl esters. The series of carbinols prepared by this method is given in Table V.I6 For comparison, the hydrocarbons, in which the hydroxyl has been substituted by the group CHI, are also given. Table V brings out a great similarity in the rotations of the hydrocarbons and carbinols. The shift of rotation with the increasing value of n2 is in the same direction in both, and in both cases the value of the optical rotation reaches a zero value. Also, in both cases there is an inversion of sign in the next higher member. It must be emphasized that in the case of the carbinols the zero value does not indicate loss of asymmetry, for the apparently inactive carbinol yields an active halide and an active hydrocarbon with one more carbon atom. In the case of the hydrocarbons it is clear that the rotation should reach zero value when the radical (CHz),,CHa reaches identity with R3; in the case of the carbinols, a minimum value is reached when nz is equal to the number of carbon atoms of the radical R3. Furthermore, at an equal distance from the asymmetric center atom, the CH3 group seems to introduce a higher contribution to the molecular rotation than the hydroxyl group, save in the case when the hydrocarbon reaches a zero value, thus indicating that at an equal distance from the asymmetric carbon atom the hydroxyl group introduces a smaller partial contribution than the methyl group, or possibly that the hydroxyl group introduces a partial rotation of direction opposite to that of the methyl group. The dispersion curve of the optically active disubstituted ethanols having n2 = 1 can be expresse; by a two-term formula, the terms being of opposite sign and XI N 1600 A, thus indicating that the hydroxyl group furnishes a partial rotation of the same direction as that of the substances in the visible region of the spectrum.17 The substances with n2> 1 show anomalous dispersion in the lower members of the homologous series and normal dispersion in the higher members, which rotate in opposite direction from the lower. Thus it is evident that in all homologous series of primary carbinols, varying with the values of n2 and n3, the hydroxyl groups furnish a partial rotation of the same direction. It may be pointed out here that for the members with 122 = 1 or 2, the rotations of the carbinols and the corresponding hydrocarbons are of the same sign, yet in each case the rotations in the visible region of the spectrum are determined by groups situated in different parts of the molecule. Thus, in the hydrocarbon (A) the rotation in the visible region is determined by the partial rotation of the C3H7 group (which is levorotatory) and that of the carbinol (B) by the group OH or CHZOH. 16

17

LEVENE,P. A., AND MARKER,R. E., J . BioE. Chem., 103, 299 (1933). LEVENE,P. A., AND ROTHEN, ALEXANDRE (unpublished results).

91


0

0

? 3 I

2 2 + t

0

n

O

au, n

n

d d

3 3

1

c! I

0

li

?

?

+

M

-

0

I

I -

0

?N 8O I

I

92

P. A. LEVENE AND ALEXANDRE ROTHEN 2

2

CH3

CH3

I

I

I

I

C3H7

C3H7

4

4

levo

levo

A

B

(The numbers indicate the order of the groups according to their increasing volume.) The observation that all lower members of the series CH3

I I

H - . C *.(CHz)n,OH C2H6 with values of n ? > l are of sign opposite to those with n2 = 1 could be shown to be due to the fact that in the former the partial contribution of the hydroxyl group has a lower numerical value and is of sign opposite to that of the sum of contributions furnished by the rest of the rn0lecule.~7

C. Carbinols of the Isopropyl and Isobutyl Series The carbinols of the isopropyl series can be correlated with the normal series by the following set of reactions.ls OR’ OR’

R1. -COOC2Hs

CH3MgBr+

HI

PH3

I .COH R1..C. HI

+

\CHs

The carbinols of the isobutyl series have been correlated with the normal series in the following mannerlg

0 A

Ri.CH-CH2

+

CH3 \ CHMgBr

/

CH3 18

---f

/CH3 R1-CH(OH).CH2C \CH,

STEVENS, P. G., J . Am. Chem. Soc., 64, 3732 (1932).

LEVENE,P. A., AND MARKER,R. E., J . BioE. Chem., 101, 413 (1933). 1 9 LEVENE,P.A., AND WALTI, A., J. Biol. Chem.. 71, 461 (1927).

93


The rotations of the members of the homologous isopropyl and isobutyl series together with the corresponding normal series are given in Table VI. Comparing the rotations of the configurationally related propylisopropyl TABLE VI AN ISOPROPYL OR ISOBUTYL GROUP SECONDARY CARBINOLS CONTAINING [MI: Max. (Homogenous) CHI

-4 C ' Ha

(CHdaCHa

1

CHI -CHrC/H 'CHI

and butylisobutylcarbinols, it can be seen that the effect of the isopropyl group is opposite in sense to that of the isobutyl group. As with the hydrocarbons, increase of the distance of the isopropyl group from the asym-

94

P. A. LEVEKE AND ALEXANDRE ROTHEN

metric center by one (CH2) group causes inversion of the sign of the partial rotation of the isopropyl group (or inversion of its vicinal effect on the hydroxyl group). It may be mentioned here that the configurations of the isopropyl and of the isobutylcarbinols had been correlated at first on the basis of the knowledge of the rotations of the propylisopropyl and butylisobutylcarbinols, combined with information on the progressive changes in rotation of the consecutive members of the two homologous series. It was argued that when the propylisopropylcarbinol is dextrorotatory, the rotations of the individual members in the homologous series progressively increase to the right and, since the members of the isopropyl series may be regarded as derived from the corresponding members of the normal series by the introduction of an additional dextrorotatory contribution, it follows that the isopropyl series is correlated to that normal series whose consecutive members increased in their rotations to the right.20 In a similar manner the configurations of the members of the isobutyl series were correlated with those of the normal butyl series. The conclusions reached in this manner were subsequently substantiated by the direct chemical method. A point of interest regarding the members of the homologous series of isopropylcarbinols is that the rotation of the first member of the series is opposite in sign to that of the higher members. I n the course of study of the rotatory dispersions of several other homologous series of substances with a chromophoric group in the near-ultraviolet region of the spectrum, it has been observed that the partial rotations of the corresponding groups always remain of the same sign throughout the homologous series. I n the case of the isopropylcarbinols, the same condition should exist. Hence the rotatory dispersion curves of the lower and the higher members should be anomalous. The anomaly, however, could not be detected.21 This failure, however, should not be attributed to the exceptional behavior of the members of the isopropylcarbinol series but rather to the fact that the absorption bands of the isopropyl radical and of the hydroxyl group are situated in the distant ultraviolet region of the spectrum so that the dispersion curves could not be extended sufficiently near to the region of absorption. Indeed, in the case of the phthalic esters of the isopropylcarbinols, no difficulty was encountered in the discovery of the anomaly in the rotatory dispersions of the higher members. LEVENE,P. A., AND MARKER, R. E., ibid., 90, 669 (1931); 97, 379 (1932). FREUDENBERG, K., Sitzber. Heidelberg. Akad. Wiss., Math.-Naturw. Klasse, 1931, 9. 21 LEVENE, P. A., AND ROTHEN,ALEXANDRE (unpublished results). 20

95

OPTICAL ACTIVITY AND STRUCTTJRE

D. Carbinols Containing an Ethylenic Group The configurational relationship of carbinols containing an ethylenic group to the saturated carbinols is readily arrived at by catalytic hydrogenation of the former. The rotations of a number of unsaturated carbinols and the corresponding saturated carbinols are given in Table VII. The significant feature of the table is that the rotations of the unsaturated carbinols are opposite in sign to those of the saturated carbinols in all cases in which the ethylenic group :is attached directly to the asymmetric carbon atom but the rotation remains in the same sense when the ethylenic group is removed from the TABLE VI1 CONFIGURATIONALLY RELATEDCARBINOLS CONTAINING A DOUBLE BOND [MI: Max. (Homogeneous) CH3

I

He C . *OH 9

I

CHz CH

I/

CHz $4.7

asymmetric center by one (CH,) group. Thus the rotations of Al-pentenol-4 and A2-pentenol-4 are in opposite directions. ThiEi change in the rotation of the molecule as a whole is associated with the change of the partial rotation of the ethylenic group. This conclusion emerges clearly from analysis of the rotatory dispersion curves of these substances, which, by virtue of the positions of their chromophoric group, permits one to extend the observations t o sufficient proximity to the absorption band and thus to obtain definite information as to the direction of the partial rotation of the double bond.22 Thus, again it is seen that with the increase of its distance from the asymmetric center by one (CH2) group, the chromophoric group changes the sign of its partial rotation. The fact that the influence of the double 22

LWENE,P. A.,

AND

ROTHEN,ALEXANDRE(unpublished results).

96

P. A. LEVENE AND ALEXANDRE ROTBEN

bond on the rotation varies with the distance of the bond from the asymmetric center has been noted by previous observers (particularly by R ~ p e ~ ~ ) but the change of sign had not been recognized before.

E. Secondary Carbinols Containing a Phenyl or Cyclohexyl Group CH3 H.-C*.OH

I

(CH2)na

I

R3 (ns = 0,l

or 2; R3 = phenyl or cyclohexyl)

1. The configurational relationship of the members of the phenyl to the cyclohexyl series can easily be determined by hydrogenation of the former. 2. The configuration of methylcyclohexyl carbinol has been arrived at by methods of classical organic chemistry,24 starting from the ester of 2-methoxypropionic acid of known configuration. The set of reactions leading to the synthesis are as follows:

OR’

cH3.

A.I .corn

BrMgCH2CHzCH2CHzCH&fgBr-+

H

OR’

oHCH2-CH2

OR’

OR’

[

Y C H -CH2 CH,. * C ** C \CH2 I \CH2-CH/ H

I

HZ -+ C H ~ . * C . . C ~ H ~ I Adams’ I catalyst H

3. The configuration of the benzyl series is arrived at through the method of the preparation of its members from the homologous ethylenic oxides of known c~nfiguration.~~ 0

A

R1.CH-CH2 23

24 25

+

BrMgCeHb + R1*CH(OH)CH2CsH5

RUPE,H., Trans. Faraday SOC.,10, 47 (1914). LEVENE,P. A., AND HARRIS,STANTON A., J . Biol. Chem., 113, 55 (1936). LEVENE,P.A., AND WALTI,A., ibid., 90, 81 (1931).


97

4. The configuration of the phenethyl series is arrived at through the following set of reactions.2b

z

I

+

CH20H dextro

In Table VI11 the rotations of the members of the normal, the cyclohexyl and the phenyl series are compared. As in the case of the isopropyl series, the configurations of the cyclohexyl series at first had been arrived at on the basis of the progressive changes in rotation of consecutive members of the normal and the cyclohexyl series. As compared with the hexyl, the cyclohexyl group for the series given in Table VI11 introduces a negative partial rotation and the negative rotation increases from member to member. Hence it is evident that in the corresponding normal aliphatic series the rotations of consecutive members likewise should increase towards the left. The conclusions arrived at on the basis of these considerations were later substantiated by the method of synthesis as given above, thus showing the validity of the theoretical speculations. The effects of the distance from the asymmetric center of the chromophoric groups are recorded in Table IX.

** LEYENE,P. A.,

AND

STEVENS, P. G., ibid., 87, 375 (1930).

THI: JOURNAL OF ORQARIC CHEMISTRY, VOL. 1. NO. 1

98


From Table IX there can be noted a periodicity in the direction of the shift of rotation with the progressive increase in the value of n3, both in cyclohexyl and phenyl derivatives. TABLE VI11 CONFIGURATIONALLY RELATED SECONDARY CARBINOLS CONTAINING A CYCLOHEXYL OR HEXYLGROUP [MI: Max. (Homogeneous) CH3

CHa

I I

I

H . .b . .OH

PHENYL,

H * C .OH CJL

L6Hl3

-52.5

$12.7

CzHs

I I

H . * C . *OH GHis +11.6

-34.9

-17.0

CaHo

C4Ho

Ha .C. *OH

H . * C .*OH

I

I

k0Hs

AaHI1

-28.2

-21.9

F . Primary Carbinols Containing a Phenyl Group CH,

H..(!3..(CH,),,OH i

C6H6 (nz= 1, 2, 3 and 4)

The configurational relationship of this group of substances follows from their origin from CH3

AI

H.

.cmH

C6Hs as in the case of primary carbinols of the normal aliphatic series.

99


x x u d g 0 -cj -u-u-u

x q

x P

Y

n t -

x

x Y D

x

x

x h

@u*

i

x" E @ u-0-u-u

x

x

x

Y

x

x

x

x

n

a

2

v

u3

2 I

100


The rotations of the consecutive members with respect to n2 are recorded in Table X.27 In this case the correlation of the configurations of the secondary carbinols with the primary is to be regarded as tentative and will not be discussed here. Among the members with nz = 1, 2 and 3 the periodicity in the shift of the direction of rotation with the increase of the value of n2 is clearly seen. 111. ACIDS, NITRILES, AND ALDEHYDES

(CH2)nJh

- I

H * C* * (CHJn,COOH

A

( H2)nrRa (General Type, Acids) (Itl,

n2 and n3 = 0, or an integer; R1 = CH3; R3 = CH3, CaHll or Cd&).

A. Conjigurational Relationships of Carboxylic Acids hawing R1and R3

=

CH, and nl = 0 Two problems presented themselves in connection with this group of substances, one dealing with the direction of rotation in series homologous with respect to 122 and the other with respect to n3. The key series of this group of substances is the series having 122 = 1. On one hand, members of this series can (through the Hofmann degradation) be converted into the acid with nz = 0. On the other hand, they can serve as starting substances for the series having n2> 1. Given two consecutive members of a homologous series, it is evident that they should lead to two enantiomeric hydrocarbons. CH3

(33.3

I

I

CH3

I

H * . C . * C O O H + H.*C**CH2COOH--j H**C*.CH&H2CH3

I

I

C2H5

C2Hs

dextTo

dextro

I

I1 CH3

dextro

I11

CH3

I

H * * C * . C O O H+

bar,

17

I

C2H6

I H**C**CH2COOH+ I

CHI

I I

H**C**CH~CHI

CaH7

C3H7

dextro

levo

kvo

VI

V

IV

LEVENE,P. A.,

AND

MARKER, R. E., ibid., 103, 299 (1933).


x

0, h

x

x

x

x

G

G

n

t:

x

G

101

102


The two hydrocarbons are enantiomeric, inasmuch as one can be derived from the other by a single permutation-it thus follows that the two parent acids (which served for the preparation of the hydrocarbons) are configurationally related. Continuing the same operations with every consecutive pair of acids, the configurational relationship of any number of members of the homologous series can be established.27s28 It may seem surprising that the method of direct conversion of the disubstituted acetic into disubstituted propionic acids was not employed for connecting the configurations of the members of the two homologous series. The method was not used, however, because in this case reduction of the esters of the acids leads to a high degree of racemization. The acids so far analyzed with regard to their configurations are recorded in Table XI. Analysis of Table XI brings out the following facts: 1. The rotations of the members of the disubstituted acetic acids remain of the same sign and their values progressively increase. 2. In the homologous series of disubstituted propionic acids, the first member differs in the sign of its rotation from the higher members and is of the same sign as the members of the acetic acid series. 3. In this series (propionic) the values of the rotations of the successive members progressively increase. 4. The rotations of the members of the homologous series with n2 > 1 decrease progressively in consecutive members. On the basis of the theory that the rotation of each substance is the algebraic sum of several partial rotations differing in their sign, the conclusion can be reached at once that in the acetic acid series the values of the positive partial rotations increase progressively, whereas in the homologous series of acids with n2 >0 the values of the negative partial rotations increase. Since the carboxyl group is the most polar group possessing absorption bands in the region nearest to the visible, it seemed logical at first to assume that in all substances recorded in Table X I this group furnished the positive partial rotation. The true meaning of the course of events emerged only from analysis of dispersion curves of this group of substances.29 At this place it may be expedient to dwell at some length on the method employed for analysis of the rotatory dispersion curves of substances resembling (with respect to the absorption regions of their chromophoric groups) the above carboxylic acids. The group -COOH possesses one absorption band at about 2050 A. Thus, on one hand, it is situated in a region which is inaccessible to LEVENE,P. A., AND BASS,L. W., ibid., 70, 211 (1926). LEVENE,P. A., ROTHEN,ALEXANDRE AND MARKER, R. E., J . Chem. Phys., 1, 662 (1933). 28

29

103


x

0 0

u_

n

9 u-u-u

t

x

x x

x

i

0

0

u,

u,

h

d 2. a (92

w

i

x

0 0

u-+-u

x

n

+

x

8

0

x

x

x

i

x

x

x

x

104


polarimetric measurements with the present-day technique, but, on the other hand, is near enough to render the extrapolation method sufficiently reliable. The method of analysis is based on the following theoretical considerations. The assumption is made that, as a first approximation, the dispersion curve at some distance from an absorption band can be expressed by two simple Drude terms. Under the dispersion curve in this instance is understood the graph of the function ( ( l / a ) ,A*). The curvature of this graph varies in a definite manner depending upon the relationship of the term &/(A2 - X12) to A2/(X2 - h2)(members of the two Drude term equation) as was definitely shown by Hunter.ao It is evident that for very small intervals of the dispersion curve it is possible to find an expression AO/(X2- Xo2) which can very nearly satisfy the righthand term of the expression

[MI = A,/(h2

- X12)

f Az/(X2 -

X22).

The value of XOand its variation with successive small wave-length intervals will provide the required information on the relative values of the four constants of the two-Drude-term formula. Four combinations have to be considered in the discussion of the relationship of the dispersion curves to the relative values of the two terms. They are as follows: Two terms of same sign (for long wave-lengths). (1)

Xl>X2[Al/(X2

-

X12)]>A2/((X2

- X22) - X22).

Xl>X2[AI/(X2 - XlZ)] X2[A1/(X2

(4)

X1>X2[A1/(X2

- X12)]>A2/(X2 - X2') - XI')]

OPTICAL ACTIVITY AND CHEMICAL STRUCTURE* - The Journal of

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