San Fernando Valley State College
S TUDIES IN ACYCLIC CONFORMATIONAL ANALYSIS
A thesis submitted in partial satisfaction of the
requirements for the degree of Master of Science in
Chemistry
by
Ezra Samuel Alhadef£
January, 1968
The thesis of Ezra Samuel Alhadeff is approved:
.
&;nunittee
Chairman
San Fernando Valley State College
January, 1968
ii
To my
parents
and to David and Michele
iii
ACKNOWLEDGEMENT
I wish to express my sincere gratitude to Professor
C.
J.
Olsen
for the aid, guidance and encouragement he gave throughout this work.
I
i
would like to express my gratitude to Professor G. M.
Nazarian for his most helpful suggestions and assistance.
I
wish to thank Professor R. A. Silva, Professor W. F.
Harrison, Professor D. 0. Skovlin, Professor K. I. Hardcastle,
•
•
Professor H. I. Abrash, Professor H. L. Nyquist, Professor V. Willis
and Professor B. Russo for their suggestions and aid.
I am indebted to many of my graduate student colleagues
J.
England, A. D. Stock, P. Bernard, B. B. Wolfe and M. H. Doll
and to my fellow student -- C. L. Tackeberry -- for the aid they
• offered.
I also wish to thank the Work-Study Program for financial
support of portions of this work.
iv
TABLE OF CONTENTS
LIST OF TABLES AND FIGURES
A BSTRACT
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vi
vii
Chapter
I.
II.
III.
IN TRODUC TION
1
5
DISCUSSION
24
EXPERIMENTAL
General
Procedures
BIBLIOGRAPHY
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•
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32
TABLE
Page
Table
1.
Experimental and Calculated . Equilibrium Constants
16
) for certain Acyclic Compounds . . .
(K
dl/meso
LIST OF FIGURES
Figure
1.
Page
Overlapped Partial Nuclear Magnetic Resonance
Spectra of meso- and dl- 1, 2-Dimethoxy1,
2.
Infrared Spectrum of �- 1, 2-Dimethoxy1,
3.
23
2 -diphenylethane
. .
2 -diphenylethane
.
.
.
.
.
.
.
.
27
Infrared Spectrum of dl-1, 2 -Dimethoxy1,
.
2 -diphenylethane
'
vi
.
.
.
.
27
ABSTRA CT
STUDIES IN A CYCLIC CONFORJVlA TIONA L ANALYSIS
by
Ezra Samuel Alhadeff
Master of Science in Chemistry
January, 1968
The isomerization of �eso- and dl- 1, 2-dimethoxy- 1, 2diphenylethane was attempted from three different approaches,
The
methods tried included isomerization by iodine free radical initiation,
catalytic hydrogenation-dehydrogenation and acid catalysis.
The
work was performed in order to gain some insight into the nature of
the factors which render diastereomers different in terms of their
thermodynamic energy content.
An entropy effect {the isotope symmetry or I S effect) is
presented which tends to favor the racemic {dl) diaster\'omer over
the meso form.
This factor, which has been overlooked by other
workers, results from symmetry considerations in view of the
natural isotope abundance of the elements.
Estimations of the effect
yield equilibrium constants which are nearly the same as certain
values which have been reported in the literature.
These experi­
mental values are now more readily rationalized in terms of the
IS effect.
vii
CHAPTER I
INTRODUCTION
This research was performed to obtain some infonnation on
. the meso - dl isomerization of a symmetrically substituted ethane,
1,
Various methods were tried in
2-dimethoxy- 1 , 2-diphenylethane.
order to reach equilibrium.
Although little work has been carried out on the meso - dl
isomerization of stereoisomers, it has been recognized for quite
some time
1
that diastereomers differ not only chemically and physi­
cally but even thermodynamically.
The energy content of a meso
compound is reported to be generally different from its corresponding
2 3
It is in order to gain more insight into the cause of this
dl pair. '
difference that determinations of the conformational energies of
different substituents are performed using techniques such as
isomerization equilibrations.
Peterson4 has recently published results on the meso - dl
isomerization of 2, 3-dimethyl-2, 3 -diphenylsuccinonitriles via a free
radical reaction at temperatures ranging from 125° to !75°, in
various solvents.
The temperature independent dl/� ratio at
equilibrium was reported to favor the dl form.
5
Ebers on had
previously reported that intramolecular hydrogen bonding in
2, 3-dimethyl-, 2, 3 -diethyl- and 2, 3-diisopropylsuccinic acids
1
2
favored the dl isomer at elevated temperatures in both aqueous and
, strong H C l media.
and Machia
·
6
A sim.ilar argument has been put forth by Bottari
in explaining the dl isomer predominance in the
2, 3-butanediol equilibrations in toluene in the presence of sodium
· followed by hydrolysis.
Abd Elhafez and Cram
7
have published results on the
erythro - threo equilibrations of 1 , 2-diphenyl - 1-propylformates at
room temperature.
A threo/erythro ratio of 0. 83 was reported at
8
equilibrium. Bartlett and McBride have recently presented a paper
indicating that the dl/� ratio for 2, 3, 4, 5 -tetramethyl- 3, 4 -
!
diphenylhexanes is near 0 . 67 at equilibrium.
The isomerization was
carried out via a free radical decomposition at 80 '.
From work
9
performed under Dr. Olsen in this laboratory it appears that free
radical isomerizations of the 2, 3-diphenylbutanes yield a similar
equilibrium constant.
Previously, Nenitzescu and Glatz
10
had also observed the
predominance of meso-2, 3 -diphenylbutane when diphenylbutanes,
---
dihalobutanes and mixed phenylhalobutanes were refluxed in benzene
in the presence of AlC 1 .
3
Their results seemed to support the
results obtained by Somerville and Spoerri
11
on 2, 3 -dipheny1butanes.
However neither group had shown strong evidence for the achievement
of equilibrium conditions.
by Hollem.an
1 2' 1 3
Equally doubtful are the results reported
on the isomerization of tartaric acids in which the
d1 pair apparently predominates.
Results obtained in isomerization
3
of erythro - threo- 3 -phenyl-2-butanols using LiA l H -AlC13 are
4
probably obscured by an unusual entropy of mixing for the threo
form.
13
Conformational equilibria have been determined principally
cycfohexane systems.
m
Kinetic, spectroscopic and equilibrium
methods have been the main approaches used in determining the
conformational equilibria.
The simplest approach is the equilibrium
method and in cyclohexane systems it involves lo-cking the ring in a
particular chair form using a bulky substituent.
by Winstein and Holness
14
As first suggested
the substituent most often used is the
tertiary butyl group generally attached at the four position.
That
substituent locks the ring in the given chair form by assuming the
preferred equatorial position.
Isomerizations have been conventionally effected by base,
Lewis acid and noble metal catalysis and by thermal and photochemical
means.
In acyclic systems the first four have been the only methods
used to date.
The first equilibration data were obtained from studies on
.
"
1.5, 16, 17
.
eye 1ohexanes us1ng Lew1s ac1ds.
Concentrated sulfuric acid
or aluminum chloride were used but they led to complex product
mixtures which could not be analyzed readily.
Hydrogenation
catalysts were later used at high temperatures and "clean"
isomerizations resulted.
18,19
When
I, I,
3, 5-tetrarnethyl-
cyclohexanes were heated over palladium, .6.H0 and .6.s• values were
4
obtained from the temperature dependence of the equilibrium
constants.
20
Sodium ethoxide in ethanol has been used at moderate
temperatures to effect the cis - !_rans isomerization of locked
21, 22
23
cyclohexyl cyan1·aes
and carboxylates.
Reversible oxidationreductions have been carried out in the equilibrations of hydroxyl
compounds over Raney nickel as well as by means of aluminum
isopropoxide
2
5 by the Meerwein -Ponndorf-Verley-Oppenauer. method
of equilibration.
CHAPTER II
DISCUSSION
In the thermodynamic treatment of the relative stability of
meso and dl diastereomers and of the related erythro, and threo
isomers, it has been assumed that the difference in free energy
between isomers is determined by the enthalpy difference only.
4
This enthalpy difference is believed to arrise from
differences in the repulsions (mostly steric and dipolar) and in the
electrostatic attractions or in the London dispersion forces between
neighboring substituents.
If the repulsive forces are the predominant
contributing factors then the meso (or the erythro) form would be
expected to be favored over the dl (or the threo) form.
other hand,
the
If,
on the
attractive forces predominate then thejl (or the
threo) form would be expected to be favored over the meso (or the
erythro) form.
·
Such an argument can be simply rationalized by assuming
that the largest groups are anti
.
conformat 1on: 2 5
in
the most populated (preferred)
5
6
L
s
M
L
M
M
s
S(S')
M
S(S')
L
meso {or erythro)
L
dl(or threo)
L, M and S represent large, medium and small groups, respectively.
The substituents1 gauche interactions can be expressed as
meso: 2
( L/M)
dl: (M/M)
+
2(L/ S)
+ (S/S)
+
+
26
2(M/ S)
2(L/M)
+
2{L/S)
The difference between the nonbonded interactions in the meso form
and the dl form is
(meso gauche) - {dl gauche)
=
2(M/S) - (M/M) -(S/S)
( 1)
If only repulsive interactions are important then the�
: forrn is favored since the steric interactions between two substituents
of unequal size are smaller than the sum of the interactions between
2 27
identical substituents. •
If however the nature of all the inter•
actions is such that any attractive force predominates, then the sign
of the derived difference(equation ( 1 ) ) is reversed and the dl pair
is favored.
Identical results are obtained in a similar treatment of
erythro - threo systems.
7
4
The entropy difference was assumed by Peterson to be zero
in the� - dl systems.
The reason given was that the value of
Rln 2 for the entropy of mixing for the dl pair is exactly canceled by
the value of - Rln 2 given by the degree of symmetry observed in�
and.!:. molecules only.
The meso molecules have a symmetry
number, <J of 1 (the symmetry is i} while the d and the 1 molecules
-
-
have a <J value of 2 (the symmetry is C ).
2
When the natural isotope abundance of the elements (especially
carbon} is taken into consideration, it is observed that the entropy
difference between the � form and the dl pair is not exactly zero
as previously stated.
This effect changes the symmetry number
of the dl pair from 2 to 1 for unsymmetrically labeled species while
it does not change the symmetry number of the meso form since it is
already 1.
The effect does not apply to erythro - threo systems
(the <J value is 1 for both diastereomers}.
This effect will be
referred to as the isotope symmetry (IS} effect.
The IS effect does
not change the value of the net difference between the entropy of
mixing for the ,.9! pair and the entropy of mixing for the�
cliastereomer although new el l species and new meso species have
been generated.
The entropies of mixing for the new species cancel
each other exactly.
Case A
-----
The mathematical treatment follows.
No IS effect:
!::.S .
m1x
=
4
- R L x.ln x. and !::. S
1
sym
1
i
=- R
.
L x.ln<J
1
1
1
.
8
where x. is the mole fraction of component i and <J", its symmetry
1
1
number.
28
For the dl diastereomer:
For the dl pair:
x
d
= x
d
=
m1x
..6. S
1.
-
1
=
0.
5
-
-
R [ 0.
2
dl
b.s
=
syrn
-R
L:
dl
=
b. s
syrn
-R
ln
0. 5
5 ln
x.ln<T. =
1
1
i=l
+
0.
5 ln
-R[ 0. 5
5
0.
ln
2
]
=
-
R
ln
+
0.
5 ln
R
ln
2
0.
2]
2
dl
= b. S .
m1x
t
dl
=
6S
syrn
R
ln
2
-
=
0
For the meso diastereomer:
m so
68 :
=
m1x
meso
=
68
syrn
0
0
}
meso
m so
68
= 68 :
m1x
since i = 1 {x. = 1 ) and
1
+
eso
68m
=
sym
O".
1
0
The total entropy difference is therefore:
..6.
[
no IS effect
65
meso-dl systems
J
d
= 65 i
_
me so
65
=
0
=
1
5 =
R ln 2
9
IS effect included:
In this case the mole fractions of the sy etrical .i and l
their values, the binomial
molecules have changed. To estimate
9
(or Bernoulli) distribution is used.2 The distribution is given by
the relation
(2)
= m! (nn! - m)! am (1 - a) n - m
. where =probability that a molecule will be isotopically labeled with
m atoms of the same mass number
n =number of atoms of the same atomic number per molecule
m =number of labelled atoms 13, H2, ) of this element
per molecule
a =natural abundance of the labelled atoms 13, H2, . . . )
The case B calculations are shown here for 1, 2-dimethoxy1, 2-diphenylethane. For that molecule it may be shown that the
probability of finding a molecule with one C13 atom is 0. 149 by
substituting into equation (2) the values n =16, m =1 and a =
0. 0 11 1. 30
Similarly, the probability of finding two c 13 atoms (m = 2)
in a molecule of 1, 2-dimethoxy-1, 2-diphcnylethane is found to be
0. 0124. However two c 13 atoms will not necessarily be located
Case B
mm
•
p
P
(C
•
.
.
(C
10
unsymmetrically· within the
i or
the
,:!. molecules
and the value
i
0. 01 24
'must be corrected for symmetrical labelling, as shown below.
The probability that the symmetry of a
, regenerated by having the two
C
13
:!_ or
an
1:. molecule
is
atoms positioned symmetrically':'
is given by the following results which consider first the probability
:of having the first
C
footnote) positions.
13
atom falling in any one of the
That probability is
13
8/ 16 1/2.
probability for the first
positions is also
the second
:if the first
• probability
c 13
c13
C
or
or
8/16 1/2.
8
"unusual" (see
While the
atom falling in the remaining "normal"
There are two available positions for
atom to fall into in order to regenerate the symmetry
atom fell in one of the "unusual" positions and the
is given as
2/15.
There is only one position for the
''There are two identical ortho positions available for a
: substitution on the phenyl rings and similarily there are two
: identical rne ta positions.
0
0
•
11unusual" positions
·
"normal" positions
'-.H
3
c 13
11
.
! -
second c13 atom to fall into in order to regenerate the symmetry
the first c 13 atom fell in one of the "normal" positions and the
probability is given as 1/15. The sum of each weighed probability is
(8/16) (2/ 15) (8/ 16) (1/ 15) 1/10
Thus one out of ten d or l molecule containing two c 13 atoms
will have a symmetry number of while the rest of the molecules
containing two 13 atoms will have a symmetry number of
Therefore out of the probability of finding two 13 atoms
within a d or an 1 molecule containing 16 carbon atoms, one tenth
should be subtracted in order to obtain the probability of finding
a molecule whose sy etry has been disrupted (whose symmetry
number has changed from 2 to 1). That probability is
0. 0 124 - 0. 00 1 24 0. 0 112
The probability of finding a molecule containing three c 13
atoms is 0. 00065 from equation
The probability of finding four c 13 atoms in one molecule
(m 4) or the probability of finding even larger numbers of 13 atoms
in one molecule is very small and for the sake of simplicity any such
contributions are ignored in the following discussion.
The total probability of finding a .sJ. or an l molecule containing
16 carbon atoms with a value of 1 is given by the sum of the
estimated probabilities
0. 149 01 12 0. 00065 0. 16 1
if
+
=
2
C
l.
C
·
-
-
mm
=
(2).
=
C
cr
+ o.
+
=
12
l
This is equal to the mole fraction of.£ and molecules with
, au value of I, while the mole fraction of.£ and molecules with a
·uvalue of 2 is I - 0.161 =0. 839.
The entropy treatment, now that the effect can be included,
. becomes
For the dl pair:
8
R
= - i=lL x.ln x.
xiICI 3In x1IC13
l
IS
1
1
-
-
x13Cl 3ln x13 CI3 ]
For the meso form:
= -Ri=IL4 x.ln x.
+
-
-
1
1
Ic13 In xIC13 xmeso
2C I3 In x2CI3
=-R [xmesoln xmeso xmeso
C13 In x3C13
3meso
J
+
+
x
�
�
+
�
13
since
(where
m:'so R ln
dl. - .6.smlX
.6.SffilX
This result for the difference between the entropies of
' mixing is identical to the result encountered in the case where the
'IS effect was not included (Case A). However the entropy difference
due to symmetry is now different as shown below:
For the dl pair:
.6.Sdlsym R 2:1 x. lno-.
-R [ 2:p xpln I x ln ]
k
=
1, 2,3, . . . )
=
=
2
8
-
i=
1
1
=
1 +
q
q
2
1
where xp is the mole fraction of the -d and - molecules whose
' symmetry has been destroyed by the IS effect and x the mole
fraction of the .3, and l. molecules whose symmetry number is still
This gives
.6.Sdlsym -R [ O.l6l ln 1 (1- 0. 161) ln 2]
3 R ln
q
2,
+
=
=
-
0. 8 9
2
14
. For the meso form:
b. Smeso = -R
sym
=
-R
=
0
I
x.lnu
I
x.ln 1
i=l
i= 1
1
1
meso
b. Sdl
= -0. 8 3 9 R ln 2
- b. S
sym
sym
meso
b. Sdl
- b. S
= R ln 2 - 0. 839 R ln 2
total
total
[
J
IS effect
= 0. 16 1 R ln 2 = 0. 112 R = b. b.s
�-dl system
If the hydrogen atoms as well as the oxygen atoms present in
[
, the molecule are given a similar but more approximate IS effect
'
i S effect
treatment,'' the value for b. b.s
dl sys tem
meso-_
.
.
·
J
is increased to the
following value
2
(number of H atoms)
molecule
2
{abundance of H )
17
(number of 0
atoms)
{abundance of
molecule
0
17
18
(number of 0
atoms)
{abundance of
molecule
0
18
= (18) {0.00016) = 0. 0029
) = {2)
{0. 0004)
= 0. 0008
) = (2)
(0. 0020)
= 0. 0040
0.0077
or
*The natural abundance of H
2
0
17
0
18
are 0. 016 per
29
cent, 0. 047 per cent and 0. 20 per cent, respectively.
,
and
0. 008
15
t;,. [!:;,.s�-dl
iS effect systemJ
=
+
ln
Since the sign is positive, the sl1 pair is favored over the
��isomer on an entropy basis. The equilibrium constant for
the meso_,... dl isomerization for l, -dimethoxy-1, -diphenylethane
, can be calculated if it is assumed that the IS effect is the only factor
, contributing to the equilibrium. This assumption is made only to
gain some insight about the magnitude of the IS effect treatment and
:it does not attempt to describe all the factors controlling the true
:equilibrium of the system. If !:;,.H is assumed to be zero, then
-T!:;,.S T ln meso____.,.. dl
and
[ t;,.smeso-dl
IS effect system J
ln
(0. 161
0.008) R
2
2
=
0. 118 R
2
'
!:;,.F
=
=
-R
K
!:;,.
K
=
R
( 3)
Equilibrium constants for systems studied previously were
calculated assuming that the IS effect was the only factor contributing
to the equilibrium. The values are tabulated (Table l) along with
actual experimental values.
On the basis of the IS effect, the dl/meso ratio is always
expected to be a number greater than one and furthermore it would
, be expected to increase with the number of atoms (especially carbon
atoms) present.
16
TABLE 1
EXPERIMENTAL AND CALCULATED EQUILIBRIUM CONSTANTS
) FOR CERTAIN ACYCLIC COMPOUNDS
(K
_meso
dl/
K
=
d1/meso
Compound
··-
e
Calculated
Experimental Reference
2, 3-dimethyl-2, 3-diphenyl-
1. 15
1. 22±0. 05
1. 06
1. 1±0. 1
1. 08
b
1. 4± 0. 1
5
1. 10
b, d
l. 4± 0. 1
5
4
succinonitrile
2, 3-dimethylsuccinic acid
a
a
2, 3-diethylsuccinic acid
2, 3-diisopropylsuccinic acid
a
1. 3±0. 1
2, 3, 4, 5-tetramethyl-3, 4-
>
b
c, d
5
5
1. 15
0. 67
8
2, 3-dipheny1butane
1. 12
0. 66
9
1,
1. 12
diphenylhexane
2-dimethoxy-1, 2-diphenyl-
-
-
ethane
This
work
.
a
·
b
The compounds are the
a,
a
1
dialkyl acids
Equilibrations in water at 170°, measured by melting point
calibration
c
Measured by potention1etric titrations
d
Ir evidence of intramolecular hydrogen bonding
e
Calculated using equation( 3)
17
The experimental data presented for the first four compounds
{ Table 1) are nearly congruent with the calculated IS effect values.
4
In Peterson's case this is not surprising since the conformational
energy of a cyano group in cyclohexyl systen1s is much smaller than
th at of even a meth y1 group.
22' 31
If
.
.
a11 other Interactions are a1so
negligible or if they all tend to cancel each other out, it leaves the
,
explanation of the observed dl predominance solely up to the IS effect.
. 5 32 33
Eberson1s studies '
'
suggested some intramolecular
hydrogen bonding in
a, a 1
dialkylsuccinic acids as an explanation of
the unusual.£!. predominance in aqueous and acidic equilibrations.
'However, comparison of calculated and experimental equilibrium
, constants { Table 1) for these compounds makes it appear unlikely
• that internal hydrogen bonding is the only significant factor in
determining the relative stabilities of Eberson1 s d1 - �eso pairs.
"·
Furthermore, the data presented by Ebers on for K /K ··· values
1
E
,
indicated that no greater internal hydrogen bonding was present
•
i
in the dl- than in the meso-dimethylsuccinic acid.
, be noted that Eberson1s reported infrared evidence
34
33
It should also
for intra-
molecular hydrogen bonding was found only for rather large alkyl
substituents and in methanol as the solvent, whereas other solvent
and K are the first ionization constant for the diacid and
E
1
the ionization constant for the corresponding monomethyl or mono­
ethyl ester, respectively. The K /K ratio is an indication of the
E
1
34
·magnitude of the internal hydrogen bonding.
*K
18
systems were used in the equilibrations.
Westheimer and Benfey
34
, had previously reported that appreciable "cyclization", in the form
i
'
'
, of hydrogen bonding, occured only in systems whose internal
'repulsions could be releaved by having large substituents assume the
anti relation to one another.
That was not observed, however, for
·molecules containing relatively smaller substituents.
It may be concluded that while intramolecular hydrogen
'bonding may be important in determining the relative stabilities of
dl - meso pairs in substituted succinic acids, it is very doubtful in
, the case of the
a,
a1
dirnethylsuccinic acid.
, hydrogen bonding is best in the case of the
The evidence for such
a,
a
1
diisopropylsuccinic
; acids where the precision of the analytical method is better than in
'
.
the dimethyl and the diethyl cases and clearly indicates that some-
: thing other than just the IS effect accounts for the greater stability of
'the dl isomer since K
1 is greater than K
expenmenta
calculated'
.
for the
K
is significantly greater than K
expenment a1
ca1cu1ated
.
diethyl case also.
However, the method of analysis (by melting point
determination) and the possibility that the equilibrium constant is
somewhat biased by the presence of even small amounts of the
corresponding anhydrides makes this particular K
exper1ment a1
.
doubtful.
It may be noted that in the case of 2, 3, 4, 5-tetramethyl-3, 4diphenylhexanes and of the 2, 3-diphenylbutanes whereas the IS effect
19
predicts a greater stability for the dl pair than for the�
diastereomer, the experimental results are actually the reverse
of this.
The results indicate that the predominant effect in deter -
mining the relative stabilities of these hydrocarbon pairs is the
difference in van der Waals repulsions in the gauche interactions of
·the preferred conformations as already noted.
It should finally be noted that caution should always be used
in attempts to explain the observed greater stability of certain ..9.!
isomers, since the I S effect alone may account for much of the
difference in stability between dl - � pairs (as shown by
K
ca1 cu1 ated
values in Table 1).
The 1, 2-dimethoxy - 1, 2-diphenylethane diastereomers
required for this research were synthesized by methylating the
corresponding dials.
method
35
The meso-dial was prepared by Dalinow's
in which benzaldehyde is reduced in the presence of zinc
and hydrochloric acid while the racemic (dl pair) dial was prepared
by the multistep procedure of Fieser.
36
Attempts at methylation by the method of Irvine and Weir
were unsuccessful.
37
The silver oxide, required in that method, was
prepared by the method of Busch, et al.
38
and by a method devised
in this laboratory whereby 2, 2-dilnethoxypropane is used as a
dehydrating agent
39
in the last step of the preparation of anhydrous
20
However a successful procedure was devised- using the
standard technique whereby a phenol is allowed to react first with
a strong base and then with dimethyl sulfate
the diethers in satisfactory yields.
40
- in order to obtain
Sodium hydride was the base
used.
Various methods were tried in order to induce the isomeri'zation of the diastereorners.
In order to obtain free radical intermediates {equation {4)),
I
2
-E:
>
2 I•
(4)
CH 0
3
. @-1, - ,1-@
0
H
CH o
3
H
OCH
+I • -E:
�
H
I I -@+HI
@-��
OCH
3
3
one of the isomers was heated, with solvents and without solvents, in
'the presence of varying quantities of iodine in evacuated ampules.
This method was shown to be effective in the isomerizations of
2, 3-diphenylbutanes.
9
Isomerization was attempted at fixed temper-
atures in the range 160° - 220°.
This procedure was unsuccessful.
The starting material was destroyed under the conditions employed
while the other isomer did not appear.
Only a number of unidentified
compounds appeared in the gas liquid chromatographic {glc) analysis.
21
Catalytic hydrogenation-dehydrogenation was next attempted
using Raney nickel.
This method involved refluxing one of the
diastereomers over Raney nickel under nitrogen gas.
The reflux
temperatures varied from about 80 o for benzene to about 140 o for
.£-xylene as solvents.
No reaction whatsoever was observed at a
reflux temperature below 1 10 o (toluene} while large amounts of
degradation products were obtained when samples were heated at
, about 140°.
'
i to
Here again the desired isomerization was not observed
have taken place although small as well as large quantities of
·such hydrogen acceptors as trans-stilbene and acetophenone were
added to promote hydrogen exchange.
Isomerization in the presence of concentrated sulfuric acid
:was tried.
One of the isomers was heated at 7 0 o to 90 o under an
:atmosphere of nitrogen and in open flasks with 25 - 50 per cent
, concentrated H2 SO4 in methanol.
i
Again extensive degradation of
the starting material was observed with no indication of isomerization.
Equation (5) shows the expected course of the reaction.
G
CH 0H
3
H
I
@-c-c-@
I I
I
H
H
@-(f)c-cI--@
0
I
I
H
(5)
22
Three n1ethods of analysis were investigated in order to
measure quantitativ ely the extent of isom erization of the
1,
2-dim ethoxy-1, 2-diphenylethanes.
The methods were l) nuclear
magnetic resonance spectroscopy 2) gas liquid chromatography and
. 3) a combination of thin layer and gas liquid chromatography.
Although the first two methods proved to be analytically f easible,
the last method was discarded because of the complexity of the
, procedure.
Overlapped partial nmr spectra of the methoxy pro tons for
!
the dl and the meso diastereomers are presented in Figure 1.
The
·
r
values as well as the broadness of the peaks were practically
unchanged when a 1:1 solution of the isomers was used.
of the peak heights at
r =
6. 7 5(dl) and at
r =
The ratio
6. 9 (meso) is at least
accurate to within 3 per c ent of the quantities of material used for
the mixed isomers' spectrum.
The m ethod selected for the present work was gas liquid
chromatography in which an accuracy of±2 per cent could be
obtained.
9
23
L--L._j___L_ L__L_L_j
6. 0
__
L__L_L___ _L_j_ _L__j__l_L__L_t___j_____L___ L_ J
__
7. 0
T
F'ig.
8.0
(ppm}
l. Overlapped partial nuc1ear magnctic resonance spectra of
f!J,esg- and 'lJ-1, 2-dimcthoxy-· 1, 2-cliphenylethane
CHAPTER
III
EXPERIMENTAL
General
All melting points were obtained on a Thomas-Hoover melting
point apparatus. The values are uncorrected and they were observed
, for samples in opened capillary tubes.
The infrared spectra (KBr) were obtained with a Beckman
IR-8 Infrared Spectrophotometer using a sodium chloride prism.
The nuclear magnetic resonance spectra were recorded on
'60 cycle Varian Associates NMR Spectrometers.
A Fortran II program was written for the G. E. 225 Computer
in order to solve equation (2) for the compounds listed in Table 1.
Proc edures
The Synthe_:;is of meso-1, 2-Dimethoxy-1, 2-diphenylethane.
An
anhydrous ether solution (500 ml) containing 10 g (0. 047 mole) of the
dry !r!_eso-1, 2 -dihydroxy-1, 2 -diphenylethane
35
was placed in a
dropping funnel attached to a three neck flask equipped with a
. magnetic stirrer, a reflux condenser and gas inlet and outlet tubes
and containing 3. 5 g {0. 15 mole) of NaH in 100
ml
of anhydrous ether.
The apparatus was flushed out with dry nitrogen and the solution, in
the dropping funnel, was added slowly over a period of 2 hours.
nitrogen inlet tube was immediately turned off, thus allowing the
24
The
25
generated hydrogen to maintain an anhydrous atmosphere within the
To the milky solution was next slowly added an excess
apparatus.
amount (60 ml) (0. 64 mole) of dimethyl sulfate.
The resulting lightly
' turbid solution was allowed to stand overnight, filtered to remove the
' insoluble materials and finally 500 ml of 6 N N H OH was added very
4
carefully while the stirred solution was kept in an ice bath.
:
The
addition of NH 0H was completed by switching to concentrated
4
' ammonia and the heat evolved in the hydrolysis of unreacted dimethyl
sulfate was sufficient to evaporate the ether.
·
The crystals, in the
aqueous solution, were air-dried, m. p. 134 o - 139 o .
The product
:was recrystallized from a l :1 mixture of chloroform and ethanol.
37
The melting point recorded was 140° - 142° (lit. m. p. : 140° - 142° ).
The yield was 4. 1 g (0. 019 mole) or 41 per cent.
The infrared
spectrum for the compound prepared in this experiment is presented
in Figure 2.
The Synthesis of dl -1, 2 - Dimethoxy-1, 2-diphenylethane.
•
The
procedure for methylating the dl-1, 2-dihydroxy-1, 2-diphenylethane
36
. to the corresponding dimethyl ether was identical to the one used for
'
the synthesis of the meso- diether with one exception.
1.
In this case
0 g (0. 0047 mole) of dried dial was used instead of 10. 0 g and the
quantities of all the reagents used were accordingly decreased by a
· factor of ten.
The melting point of the crude product was 84° - 89°
and after recrystallyzation from 95 per cent ethanol it was observed
: to be 91
o -
92 o (lit. m. p.
41
: 91 o
-
92 ° ) .
The yield was 0. 38 g (0. 0018
26
mole) or 38 per cent.
The infrared spectrum for the compound
prepared in this experiment is presented in Figure 3.
The Attempted Thermal Isomerization of l , 2-Dimethoxy-l, 2diphenylethane in the Presence of Iodine.
Samples of the meso
diastereomer, ranging from 20 mg up to 50 mg, were sealed with
iodine (from 0. 0 mg up to 50 mg) in evacuated ampules.
The ampules
'were filled with nitrogen between evacuations to insure that the
The
samples would be oxygen free prior to the final evacuation.
ampules' were suspended in baths maintained at 159. 2 o
179. 9o
±
0. 5° and 220°
±
±
0.
l o,
3° .
The ampules were removed periodically and allowed to cool
down to room temperature.
The necks were cracked open and
0. 3 - 0. 5 ml of CHC1 was added to the dark residues.
3
The solutions
were stirred and allowed to stand for about one hour before injecting
them onto the gas liquid chromatograph(glc).
The unreacted iodine
did not interfere with the glc analysis as indicated by the results
obtained for samples from which the iodine was extracted with an
aqueous sodium hydrosulfite solution prior to injection.
Similar runs were carried out using diphenyl ether and
,
g-hexadecane as solvents.
For some of the samples, a few drops of
CHC1 were added to the solvents just prior to injection to increase
3
the rate of dissolution of the residues, while for other samples small
portions of the solutions were injected directly onto the glc.
1!� I!
�l.l I
II
4000
3500
3000
Fig. 2
4000
3500
3000
Fig. 3
'
2 500
2000
2000
1
1500
" IM
Ill,
Ill
'
� �� ·� n �
1000
v
CM·•
600
Infrared spectrum of �-1,2-dirnethoxy-1,2-diphenylethane (KBr)
2500
2000
2000
1500
1000
\j
'
CM·
600
Infrared spectrum of £L-1,2-dimethoxy-1,2-dipheny1ethane (KBr)
"'
....,
28
A glc analysis of the crystalline� enantiomer which was
heated, without iodine, at 220°, indicated that a series of degradation products had been obtained.
When the compound was heated,
with an equal weight of iodine and at the same temperature, a larger
number of degradation products was obtained although the expected
isomerization was not observed to have taken place.
When the meso
---
isomer was sealed under vacuum in the presence of an equal amount
of iodine and left for over two days at room temperature, again a
series of degradation products was observed.
When the meso isomer
was heated, without iodine, at 159 o, a single compound(corresponding to the unreacted starting material) was identified.
However,
when iodine was added at that temperature, a large amount of
degradation products was observed.
These products were not
identified.
Similar products were obtained when the isomer was heated
in solutions of solvents such as n-hexadecane and diphenyl ether.
The Attempted Thermal Isomerization of 1, 2-Dimethoxy-1, 2diphenylethane over Raney Nickel.
Raney nickel was prepared
42
by Vogel's procedure
and stored under absolute ethanol.
About
20 g of the freshly prepared Raney nickel suspension was rinsed
twice with benzene and the remaining ethanol was azeotroped off in
a benzene distillation.
31
The resulting Raney nickel was stored under
benzene and needed portions were rinsed, with the appropriate
solvent, three times before each run.
29
Samples of meso-1, 2-dimethoxy-1, 2-diphenylethane {50 mg)
were heated at about 80°, 110° and 140° in refluxing benzene, toluene
and p-xylene, respectively, in the presence of 0. 1 - 0. 2 g of
thoroughly rinsed Raney nickel and 0. 5 - 60 mg of trans-stilbene
or 5 - 10 mg of acetophenone.
At intervals varying from 1 hour to
24 hours under reflux, small samples were withdrawn and injected
onto the glc.
For the experiments performed at temperatures below 110•,
no loss of the meso isomer was observed {although the trans-stilbene
---
---
and the acetophenone underwent hydrogenation).
At temperatures
near 140 • large quantities of degradation products were obtained.
The products were not identified.
The Attempted Thermal Isomerization of 1, 2-Dimethoxy-1, 2diphenylethane with Concentrated Sulfuric Acid and Methanol.
Nearly 18 mg portions of the meso isomer were dissolved in 3 ml
portions of methanol.
From 1 to 3 ml of concentrated H so were
2 4
added slowly while cooling and the resulting solutions were heated
under nitrogen as well as in open flasks at temperatures. varying
from 70 • to 90 •.
At intervals ranging from about 15 min. up to
24 hours after immersion in the heat baths, small portions of the
solutions were withdrawn and injected onto the glc.
The meso isomer was destroyed in every single run while
again a set of degradation products was observed in the glc analysis.
The products were not identified.
30
••
The Gas Liquid Chromatographic Analysis of the Isomerization of
1, 2-Dimethoxy-1, 2-diphenylethane.
A 22 foot x 1/4 in. o. d.
column packed with 5 per cent Viton on 70-80 mesh Chrornosorb G
was placed in an F&M model 720 Dual Column Programmed
Temperature Gas Chromatograph equipped with a disc chart
.
integrator.
The column was maintained at 185 o
of 70 to 80 ml/min.
±
1° with a flow rate
The injection port was kept near 3 60°.
An
almost complete resolution of the meso and dl peaks was observed
under these conditions with the meso peak appearing first, about
20 min. following injection of the solution.
The Nuclear Magnetic Resonance Spectroscopic Analysis of the
Isomerization of 1, 2-Dimethoxy-1, 2-diphenylethane.
The
nuclear magnetic spectra were recorded on 60 cycle Varian Associates
NMR Spectrometers by Professor Silva and by Mr. P. Bernard.
The
diastereomers (40 mg) were dissolved in deuterated chloroform and
tetramethyl silane was used for calibration of the instruments.
The Combined Thin Layer - Gas Liquid Chromatographic Analysis
of 1, 2 -Dimethoxy-1, 2 -diphenylethane.
The isomers were
separated by thin layer chromatography using Silica Gel G and
ethanol-free chloroform.
The� fonn r value was near 0. 48
f
while the dl pair r value was near 0. 28.
f
The outlined silica gel
areas were separately drawn by vacuum into filter paper thimbles and
the organic components were extracted from the silica gel with small
31
portions of CHC1 .
3
The solutions were evaporated down to 0. l- 0. 2
ml and injected separately on
a
6 foot Silicone Gum Rubber column
maintained at 180° and at a flow rate of 75-80 ml/min.
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