CONFORMATIONAL ANALYSIS OF
SUBSTITUTED PHENYLACETALDEHYDES
BY NUCLEAR MAGNETIC RESONMCE
SPECTROSCOPY

Thesis for the Degree of Ph. D.
MICHIGAN STATE UNIVERSITY
DONALD WILLIAM BUSHMAN

1 97 1

 

J‘JC‘: N

LIBRA It, 3.

‘j ‘MichiganStatc

University

 

This is to certify that the

thesis entitled

Conformational Analysis of Substituted
PhenyZacetaZdehydes by Nuclear Magnetic
Resonance Spectroscopy

presented by

Donald W ZZiam Bushman

has been accepted towards fulfillment
of the requirements for

 

 

[f Kim/s1;

Major professor
G. J. Karabatsos

 

Date 29 JulyJ 1.971

 

 

ABSTRACT

CONFORMATIONAL ANALYSIS OF SUBSTITUTED PHENYLACETALDEHYDES BY
NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

By

Donald William Bushman

Nuclear magnetic resonance spectroscopy has been used in the conform-
ational analysis of substituted phenylacetaldehydes. The time averaged
vicinal spin-spin coupling constants between the aldehydic and a-protons
of phenylacetaldehyde, pfmethylphenylacetaldehyde, p;methoxyphenylacetal-
hyde, pfchlorophenylacetaldehyde, 2,6-dichlorophenylacetaldehyde, and
phenylmercaptoacetaldehyde were studied at 60 MHz as a function of
temperature and solvent. The data for the substituted phenylacetaldehydes
were interpreted in terms of conformations I and II, in which a single
bond eclipses the carbonyl group. The analysis of the data led to the

following conclusions for the substituted phenylacetaldehydes. l) Conform-

H 0 R 0

// \ //
\

ation II has a lower enthalpy than I in solvents of high dielectric
constant, 2) as the dielectric constant of the solvent is increased the

stability of II relative to I increases, 3) the free energy differences for

Donald William Bushman
I 3 II are solvent dependent, being more negative in solvents of high
dielectric constant, and 4) local dipole-dipole interactions are more
important in determining rotamer stability than overall dipole-dipole
interactions.

The following conclusions were drawn for phenylmercaptoacetaldehyde.
l) Conformation I is favored by enthalpy relative to II in all solvents
studied, 2) as the dielectric constant of the solvent is increased the
stability of 1 relative to II decreases, 3) the free energy differences
for I 3 II are solvent dependent, being more positive in solvents of low
dielectric constant, and 4) the local dipole-dipole interactions are
more important in determining rotamer stability than overall dipole-
dipole interactions.

Chemical shifts of the aldehydic and methylenic protons were also
measured in conjunction with the coupling constants. It was found that
the chemical shift results are in agreement with a recent model for the
anisotropy of the carbonyl group. These data also reinforce the
conclusion derived from the coupling constant data concerning the

stability of the rotamers, I and II.

CONFORMATIONAL ANALYSIS OF SUBSTITUTED PHENYLACETALDEHYDES BY
NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

By

Donald William Bushman

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

I971

TO MOM AND DAD
AND
M, P, K, A, B,

J,P,C,N,J,..

ii

ACKNOWLEDGMENTS

The author wishes to express his sincere appreciation to
Professor G. J. Karabatsos for his help, patience, and friendship during
the course of this investigation. He also wishes to thank Professor
Karabatsos and the members of his research group for many stimulating
conversations, especially those outside the world of chemistry.

The author also wishes to express his appreciation to the Department
of Chemistry of Michigan State University for providing the opportunity
to gain teaching experience and the National Science Foundation for
financial assistance.

Finally, the author would like to thank Local Board No. 76 for
ensuring the author's employment in spite of the present economic
conditions, Army ROTC for providing two all expense paid summer vacations
in the sun, Ronald Erlich for provocative discussions on sex and the
single American female, Joseph McGrath for his collaboration on

experiments concerning the effects of ethanol on homo sapiens, and women

 

in general, who appear to be the waste of an otherwise good rib. A
special thanks to the author's parents, without whom the author and

this work would have been virtually impossible.

Die Gedanken sind frei!

Wer kann sie erraten?

Sie fliehen vorbei

wie nachtliche Schatten.
Kein Mensch kann sie wissen,
kein Jager erschiessen,

es bleibet dabei:

Die Gedanken sind frei!

Volksweise aus der
Schweiz um l815

iv

TABLE OF CONTENTS

INTRODUCTION ............................ l
RESULTS .............................. 5
A. Spin-Spin Coupling Constants ............... 5

B. Chemical Shifts ...................... l9
DISCUSSION ............................ 29
A. Spin-Spin Coupling Constants ............... 3l

B. The Effect of Solvent Polarity on Rotamer Stabilities . . .41

C. Chemical Shifts ...................... 47
EXPERIMENTAL ............................ 49
A. Reagents and Compounds .................. 49

B. Solvents ......................... 49

C. Synthesis ......................... 49

I. prethylphenylacetaldehyde .............. 49

II. prethoxyphenylacetaldehyde .............. 50

III. p;Chlorophenylacetaldehyde .............. 5l

IV. 2, 6- Dichlorophenylacetaldehyde ............ 5l

V. Phenylmercaptoacetaldehyde .............. 52

D. N. M. R. Spectra ...................... 53
REFERENCES ............................. 54

LIST OF TABLES

Table Page

I. Vicinal Spin-Spin Coupling Constants, in Hz, of Substituted
Phenylacetaldehydes and Phenylmercaptoacetaldehyde ..... 6

II. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant of Phenylacetaldehyde ..............

111. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant of pyMethylphenylacetaldehyde .......... 8

IV. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant of prethoxyphenylacetaldehyde .......... 9

V. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant of pyChlorophenylacetaldehyde .......... l0

VI. Temperature Dependence of the Vicinal Spin—Spin Coupling
Constant of 2,6-Dichlorophenylacetaldehyde ........ ll

VII. Temperature Dependence of the Vicinal Spin—Spin Coupling
Constant of Phenylmercaptoacetaldehyde .......... l2

VIII. Solvent Dependence of the Chemical Shifts of Substituted
Phenylacetaldehydes and Phenylmercaptoacetaldehyde . . . . 20

IX. Temperature Dependence of the Chemical Shifts of
Phenylacetaldehyde .................... 22

X. Temperature Dependence of the Chemical Shifts of
prethylphenylacetaldehyde ................ 23

XI. Temperature Dependence of the Chemical Shifts of
p;Methoxyphenylacetaldehyde ................ 24

XII. Temperature Dependence of the Chemical Shifts of
pyChlorophenylacetaldehyde ................ 25

XIII. Temperature Dependence of the Chemical Shifts of
2,6-Dichlorophenylacetaldehyde .............. 27

XIV. Temperature Dependence of the Chemical Shifts of
Phenylmercaptoacetaldehyde ................ 29

XV. Solvent Dependence of the Relative Rotamer Populations of
Substituted Phenylacetaldehydes .............. 34

vi

XVI. Solvent Dependence of the Free Energy Differences, AG°,
Between Rotamers of Substituted Phenylacetaldehydes . . . . 35

XVII. Solvent Dependence of the Enthalpy Differences, AH°,
Between Rotamers of Substituted Phenylacetaldehydes . . . . 37

XVIII. Solvent Dependence of the Relative Rotamer Populations
of Phenylmercaptoacetaldehyde ............... 38

XIX. Solvent Dependence of the Free Energy Difference, AG°,

and the Enthalpy Difference, AH°, Between Rotamers of
Phenylmercaptoacetaldehyde ................ 39

vii

LIST OF FIGURES

Figure Page

I. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant for Phenylacetaldehyde ............... l3

2. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant for prethylphenylacetaldehyde ........... l4

3. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant for p;Methoxyphenylacetaldehyde .......... l5

4. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant for p;Chlor0phenylacetaldehyde .......... l6

5. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant for 2,6-Dichlorophenylacetaldehyde ......... l7

6. Temperature Dependence of the Vicinal Spin-Spin Coupling
Constant for Phenylmercaptoacetaldehyde ........... l8

viii

INTRODUCTION

Many techniques have been used in the investigation of rotational
isomerism about carbon-carbon single bonds. Particular attention has
been paid to the relative stabilities of rotamers in systems such as
I. The relative stabilities of rotamers £3 and go, and 3 have been

studied with respect to rotation about the carbon-carbon bond joining the

 

X
I.
Y
sp2 and sp3 hybridized carbons as a function of X, Y, and R. These in-

vestigations include Raman and infrared studies of a-haloacetones

H X

\ /\ //”\ //
(I \ {I \ ,I \

Y H Y H H Y
a 2b
’VL

"Vb

8w

(l,2,3), haloacetylhalides (4,5), and a-haloacetaldehydes (6);

microwave studies of acetaldehyde (7), acetone (8), pr0pionaldehyde (9),
fluoroacetyl fluoride (l0), and olefins (ll,12); electron defraction
studies of aliphatic ketones (l3) and aldehydes (l4,l5,l6); and

l

2

nuclear magnetic resonance studies of ketones (l7), 3-substituted
pr0pylenes (18-22), hydrazones (23,24,25), and aldehydes (26-31).

Several basic factors have been proposed to explain the results
of many of these investigations. Included among these factors are
nonbonded (attractive and repulsive), dipole-dipole, dipole-induced
dipole, and electrostatic interactions. Thus, nonbonded repulsions
between R and Y as well as electrostatic dipole-dipole interactions in
rotamers 2a and 2p have been used to explain the different
2(a and p)/3 ratios in chloroacetone (l) and chloroacetyl chloride (4).
In agreement with this hypothesis are reports using I.R. techniques
(6.28). that chloroacetaldehyde exists essentially in conformation 2,
conformer 2 being about 300-l500 cal/mole more stable than 3
according to AH° values. However, N.M.R. results (28) have shown 3
to be more stable than 2. It has been shown (29) that in nonpolar
solvents g for dichloroacetaldehyde is about 300 cal/mole more stable
than 3 according to AH° values. In polar solvents, however, dipole-
dipole interactions become sufficiently important in dichloroacetaldehyde
to make 3 more stable than 2 by 4SO-l4OO cal/mole according to AH°
values. Since both conformers g and 3 are present in chloroacetone,
it might be concluded that nonbonded interactions between R and Y
significantly affect the relative stabilities of 2 and 3. In contrast,
nonbonded interactions play minor roles on the stabilities of rotamers
of aldehydic systems (X = 0, Y = H, and R = alkyl or aryl) (27). For
example, AH° for g z 3 is -800 and -500 cal/mole when R is methyl or
isoprOpyl, respectively. When R is methyl, less than 200 cal/mole of
the 800 cal/mole is due to nonbonded repulsions. Nonbonded repulsions
only become significant when R is t:butyl, in which case 2 is favored

over 3 by 250 cal/mole.

3

Although for discussion purposes the threefold barrier to
rotation is considered and Spoken of as having perfectly eclipsed
minimum energy conformations, we recognize that N.M.R. techniques
cannot detect small deviations in the dihedral angle (27,32).

Previous work (30) has indicated that dipole-induced dipole
interactions do not play major roles in determining the relative
stabilities of 4a, 4b, and 5. However, since dipole-dipole interactions
may be significant and since logical substrate choices such as chloro-
and bromoacetaldehydes suffer from nonbonded interactions, it is
interesting to study the rotational isomerism in substituted phenyl-

acetaldehydes to see the effect of such substitution on the relative

H O H O

\ / \ //° \ //
A \ {I \ \

H R H H H H
4a 4b 5

«A. mm .b
stabilities of 4 and 5. Two possibilities immediately come to mind:
I) that the dipole of the entire group, R, (i,e,, phenyl and
substituent) will affect the relative stabilities of 4 and 5 or 2)
that only local dipole-dipole interactions are important and therefore,
substitution should not greatly affect the relative stabilities of 4
and Q.

The effect of the anisotropy of the carbonyl group has been the
subject of investigations in recent years (33.34). A model, Q,

described by Jackman (35) has been widely accepted; however, a more

4

refined model, 1, has recently been suggested (36). In order to

 

 

 

 

 

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determine the agreement of the newer model, 1, with experimental

results, the chemical shifts of the substituted phenylacetaldehydes

and phenylmercaptoacetaldehyde were also measured.

RESULTS

A. Spin-Spin Coupling Constants

 

The vicinal spin-spin coupling constants for the substituted
phenylacetaldehydes and phenylmercaptoacetaldehyde are summarized in
Table I. The coupling constants were measured in 5% (vol./vol. for
liquids or wt./wt. for solids) solutions in the various solvents and
are an average of six to ten measurements with a precision of :0.03 Hz.
They were checked for accuracy against the known values (26,37) of
acetaldehyde; 2.85, 2.88, and 2.90 Hz at 36, O, and -30°, respectively.

The coupling constants of the phenylacetaldehydes proved to be
smaller than those of acetaldehyde, as are those of monosubstituted
alkyl acetaldehydes (27). These decreased with increasing dielectric
constant of the solvent, except in the case of 2,6-dichlorOphenylacetalde-
hyde which behaved erratically. In contrast, the coupling constants
for phenylmercaptoacetaldehyde were larger than those of acetaldehyde
and again decreased with increasing solvent dielectric constant.

The temperature dependence of the coupling constants are given
in Tables II, III, IV, V, VI, and VII. Plots of the coupling constants
versus temperature are given in Figs. l, 2, 3, 4, 5, and 6. The
coupling constant of phenylacetaldehyde decreased with increasing
temperature in cyclohexane and decalin, was constant in ethyl ether,
and increased in methylene bromide, dimethyl formamide, and benzonitrile.
As may be seen in Fig. l, the coupling constant for phenylacetaldehyde

becomes independent of temperature at a value of 2.40 Hz. The same

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trends are noted in the case of p;methylphenylacetaldehyde, Fig. 2,
the coupling constant becoming temperature independent at a value of
2.30 Hz. In pfmethoxyphenylacetaldehyde, the coupling constant remained
constant in ethyl ether and tetrahydrofuran, but increased with
increasing temperature in methylene bromide, dimethyl formamide, and
benzonitrile. It also becomes temperature independent at a value of
2.40 Hz as seen in Fig. 3. The coupling constants for pfchlorOphenyl-
acetaldehyde and 2,6-dichlorophenylacetaldehyde increased with increasing
temperature in all solvents studied. The coupling constant of
p;chlorophenylacetaldehyde appears to become temperature independent
at 2.20 Hz as shown in Fig. 4. The coupling constant for 2,6-dichloro-
phenylacetaldehyde is considerably smaller than those of the other
phenylacetaldehydes and appears to become temperature independent at
l.35 Hz as shown in Fig. 5. The coupling constant for phenylmercapto-
acetaldehyde decreased with increasing temperature in all solvents
studied, except in dimethyl formamide, where it remained constant. The

coupling becomes temperature independent at 2.75 Hz, Fig. 6.

B. Chemical Shifts

 

Summarized in Table VIII are the solvent dependencies of the
chemical shifts of the aldehydic and methylenic protons of the
substituted phenylacetaldehydes and phenylmercaptoacetaldehyde. The
chemical shifts were measured in 5% (vol./vol. for liquids or wt./wt.
for solids) solutions using tetramethylsilane as an internal standard.
The values were calibrated at a sweep width of lOOO Hz using a known
sample of tetramethylsilane (0.0 Hz), cyclohexane (86.0 Hz), acetone
(l26.7 Hz), l,l,l-trichloroethane (l64.0 Hz), dioxane (2l7.0 Hz),
methylene chloride (3T8.0 Hz), and chloroform (439.8 Hz).

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2l

The chemical shifts of the aldehydic and methylenic protons moved
to lower fields as the solvent polarity increased. Those of the
methylenic protons, however, underwent a much larger change than those
of the aldehydic proton in all compounds studied, except 2,6-dichloro-
phenylacetaldehyde.

The temperature dependence of the chemical shifts of the
phenylacetaldehydes is given in Tables IX, X, XI, X11, and XIII. With
increasing temperature, the chemical shifts of the methylenic protons
of the parafsubstituted phenylacetaldehydes remained constant or were
shifted downfield in solvents of low dielectric constant and upfield
in those of high dielectric constant. The chemical shifts of the
aldehydic protons remained constant or were shifted downfield with
increasing temperature. For 2,6-dichlorophenylacetaldehyde, the chemical
shifts of the methylenic protons and of the aldehydic proton were
shifted upfield with increasing temperature, regardless of solvent
dielectric constant.

The temperature dependence of the chemical shifts of phenylmercapto-
acetaldehyde is given in Table XIV. With increasing temperature, the
chemical shift of the methylenic protons moved downfield in solvents
of low dielectric constant and upfield in those of high dielectric
constant. The chemical shift of the aldehydic proton remained constant

or was shifted downfield with increasing temperature.

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24

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25

 

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28

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29

 

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DISCUSSION

A. Spin-Spin Coupling Constants
The data in Tables I, II, III, IV, V, VI, and VII have been
interpreted in terms of an equilibrium between rotamers 4 and 5. It
is assumed that J > J , where J
t g t
is the gauche. The observed coupling constant would be temperature

is the trans coupling constant and J9

independent if 4a, 4b, and 5 were isoenergetic. If 4a were more stable

\ //“\ IX //
A \ A \ A \

H R H R H H H H H
4a 4b

\ ,q, ’ \J’\,

801

than 5, the observed vicinal coupling constant would decrease with
increasing temperature; conversely, it would increase with increasing
temperature if 4a were less stable than 5. The following conclusions
can be drawn from the temperature dependence of the spin-spin coupling
constants of the aldehydes investigated: l) The rotamers of phenyl-
acetaldehyde are isoenergetic (i,g,, no change in the observed coupling
with temperature) in solvents of low dielectric constant. However, in
solvents of high dielectric constant, the most stable rotamer is 5.

2) In solvents of low dielectric constant, rotamer 43 of pfmethylphenyl—

3l

32
acetaldehyde is more stable than’5. In solvents of intermediate
dielectric constant, such as ethyl ether and tetrahydrofuran, 55 and
5 are isoenergetic. In solvents of high dielectric constant,,5 is
the more stable rotamer. 3) For pfmethoxyphenylacetaldehyde, 55
and 5 are isoenergetic in ethyl ether and tetrahydrofuran, whilel5 is
more stable in solvents of high dielectric constant. 4) For pfchloro-
phenylacetaldehyde in cyclohexane or transfdecalin, 55 and 5 are
isoenergetic at or above 38°, but in solvents of higher dielectric
constant, 5 is more stable than 55. 5) For 2,6-dichlorophenylacetaldehyde,
5 is more stable than 55 in all solvents studied. 6) For phenylmercapto-
acetaldehyde, 35 is more stable than 5 except in dimethyl formamide
where they are isoenergetic.

Rotamer populations were calculated using equation l, where Jobsd

Jobsd = put + .1ng + (1-pwg m

is the observed coupling constant, p is the fractional population of

4 (4a + 55), and (l-p) that of 5. Free energy differences, AG°,

'b’Vb
between $5 and 5 were calculated from equation 2. The enthalpy

AG° = -RTln(J + J - 2d

t g obsd)/(J

obsd - Jg) (2)

differences, AH°, between 45 and 5 were obtained from plots of log Keq
versus l/T, where Keq is the equilibrium constant given by equation 3.

Keq = 2(l-p)/p (3)

For the above calculations, the values of Jt and J9 must be known
or estimated. For systems with large changes in Jobsd’ limits for

Jt and 09 may be set using equation 4, which relates the experimental

CC = (”Wt + 2,9) (4)

33

coupling constant to Jt and J9, either when the rotamers are equally
populated, or at free rotation about the carbon-carbon single bond
(usually at very high temperatures).

In cases, such as those investigated here, where the changes in
Jobsd are relatively small, such estimates are not easily made. Since
J

t
respectively, the temperature independent value of the coupling constant

and 09 for acetaldehyde have been estimated (27) as 7.6 and 0.5 Hz,

can be used to estimate the correction needed to be applied to the
observed couplings to allow the use of Jt and 09 of acetaldehyde in
equations l and 2. The temperature independent values for phenyl-
acetaldehyde, pfmethylphenylacetaldehyde, pymethoxyphenylacetaldehyde,
pfchlorophenylacetaldehyde, 2,6-dichlorophenylacetaldehyde, and
phenylmercaptoacetaldehyde are 2.40, 2.30, 2.40, 2.20, l.35, and 2.75 Hz,
respectively. Using a value of 2.85 Hz for the coupling constant of
acetaldehyde, the applied corrections are +0.45, +0.55, +0.45, +0.65,
+l.50, and +0.l0 Hz, respectively.

Using the above method, the effect of the solvent dielectric
constant on the relative populations of 4 and 5 for the substituted
phenylacetaldehydes studied was determined. The results of these
calculations are given in Table XV. Since the temperature independent
coupling constants for pfchloro- and 2,6-dichlorophenylacetaldehyde are
lower than those usually found for monosubstituted aldehydes, the
calculations for these compounds were also performed as if the
temperature independent coupling constants for both were 2.40 Hz.

As noted previously from the coupling constant data, the population of
5 increases as the solvent dielectric constant increases. This same
effect can be seen in Table XVI in terms of the free energy differences,

AG°, calculated from equation 2. The enthalpy differences (AH°)

34

 

 

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CN CC CC CC CC CC CC CCCCCC
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NN CC CCNACCCC
CC CC CC CC NC CC NC NCCNCC
NN NC CC CC CC CC CCC
CC CC CC CC CC CN CC CNANCCCCCC
NC NC CC CC CN NC CCCCCCCLCCCCM
NC mm mm Cm NN Nm CCmeCoCCCC
CC Cq Cm C< Ccm>Com

CC CC CC .C CC
CCCNCCCCNCC-C.N CCCNCCCCCCNN CCCNCCCCCCCCNC CCCNCCCCCCCNC CCCNCCCC

 

CCCCCCCCCCCCCCCCCCC CCCCCCCCCCC CC

0

CcoCCCCCCoC LCECCCC C>CCC_CC CCC Co mucmvcmqmo Ccm>Com

.>x mpnmp

35

umno

 

 

 

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CCCC- CCN- CCC- CCN- CCC- CCC- CCN- CCCCCC
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CCCC- CCC- CCNACCCC
CCC- CCC- CCN- CCC- CCC- CN- CCC- NCCNCC
CNCC- CCN- CCC- CCC- CC+ CN- CCC
CCC- CCC- CCN- CN- CN+ CCC+ CC+ CNANCCCCCC
CNC- CCC- CCC- CN- CCC+ CC+ CCCCCCCCCCCHH
CCC- CNC- CCC- CN- CNC+ CC+ CCCCCCCCCCC

CC CC CC CC CCCCCCC
C C CC CCC C C CC CCC w C CC CCC w M CC CCC W n Cw CCC
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36
between 4 and 5, determined from reasonably linear plots of log Keq
versus l/T, are given in Table XVII. The effect of solvent dielectric
constant on the relative populations of 5 and 5 for phenylmercaptoacetalde-
hyde are given in Table XVIII. The free energy differences, AG°, and
the enthalpy differences, AH°, between 5 and 5 are given in Table XIX.

The relative stabilities of rotamer 5 compared with 45 for the

monosubstituted acetaldehydes studied here and previously (27,28,30) are:

70
I

- CH3 > CH3CH2 t 0C6H5 m 0CH3 > CH(CH3)2 > CT > 2,6-(Cl)2C6H3

8

EfCIC6H4 :C6H5 % 27CH30C6H4 % EfCH3C6H4 % Br > C(CH3)3 > SCH3

. SC6H5

J

This order is only valid in solvents of low dielectric constant, such

as cyclohexane or transrdecalin. In solvents of high dielectric
constant, the methoxy, phenoxy, chloro, and bromo groups become more
effective than the methyl group in the above order. The position of the
more polarizable methylmercapto group with respect to that of the less
polarizable methoxy group, along with that of bromine with respect to
chlorine, has been used to show that dipole-induced dipole interactions
play only a minor role in determining the relative stabilities of 5 and
5 (30). Nonbonded repulsions are partly reSponsible for the positions
of the bulky t7butyl and methylmercapto groups. However, their relative
positions (30) reinforce the conclusion (27) that nonbonded repulsions
are not the overriding factor controlling rotamer stability. From the
great similarity in AG° and AH° values between the para:substituted
phenylacetaldehydes in a given solvent, it appears that overall dipole-
dipole interactions are not a major factor determining rotamer stability,
but rather only local dipole-dipole interactions are important. Since

the AG° and AH° values for 2,6-dichlorophenylacetaldehyde are more

37

. . CCCo CCCo
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CCC- CCC- CCC- CNC- C CCC
CCC- CCC- CCCC- CC__. C C C CNCNCCCCCC
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m

Table XVIII.

38

Solvent Dependence of the Relative Rotamer Populations

of Phenylmercaptoacetaldehyde

a

 

 

PhSCHZCHO

Solvent a?
cyclohexane l9
trans-decalin l9
(CH3CH2)20 22
THF 27
CHzBr2 22
(CH3)2NCHO 33
C6H5CN 29

 

8All values

calculated for 5% solutions at 38°.

39

Table XIX. Solvent Dependence of the Free Energy Differencea, AG°, and
the Enthalpy Differenceb, AH°, Between Rotamers of

Phenylmercaptoacetaldehyde

 

 

PhSCHZCHO
AGO, cal/mole, AH°, cal/mole,
forum forsezé
Solvent
cyclohexane +4l5 +l670
trans-decalin +4l5 +l050
(CH3CH2)20 +3l0 +540
THF +l65 +440
+ +
CH28r2 3l0 660
(CH3)2NCHO +l0 +l00
C6H5CN +llO +500

 

aThese values Here calculated from the corresponding data at 38° in
Table XVIII. These values were obtained by plotting the natural
logarithm of the equilibrium constants calculated from the rotamer
populations versus l/T.

40
negative than for the pgrg:substituted phenylacetaldehydes, overall
dipole-dipole interactions are probably not important; and this difference
may be due to attractive interactions between the chloro and the
carbonyl groups.

For pfchloro— and 2,6-dichlorophenylacetaldehyde, the rotamer
populations, AG°, and AH° were also calculated as if the temperature
independent value of Jobsd were 2.40 Hz. Although AG° values are
sensitive to J

obsd’ AH° values are less so. There appears to be no

reason to assume that all the compounds studied should have the same

 

temperature independent value. If rotamers g and Q are considered, the
temperature independent value of Jobsd is a function of the energy

wells for the rotamers of the system. If the energy wells for g and 3

O
I

O R

I. .

H H

fé 2

are broad, then Jobsd will become temperature independent at lower
temperatures (accessible to experimental measurement) than if the
reverse were true. Thus, the temperature independent values of Jobsd
may have different values due to the effect of the substituents on
the shape of the energy wells describing the system.

The possibility of a twofold barrier to rotation may be eliminated

by considering rotamers é and IQ as the equilibrium conformations. The

41

relevant vicinal Spin-spin coupling constants would be J (60°) from 5

9

I
O

and 01200 from IQ. For a twofold barrier to rotation, equation 4 becomes

equation 4'. From the observed coupling constants, J must be equal

9

Jobsd = (1/2)(Jg + J1200) (4')

to or smaller than l.84, 1.85, 2.05, l.47, and 0.52 Hz for phenyl-,
p;methylphenyl-, p;methoxyphenyl-, pfchlorophenyl-, and 2,6-dichloro-
phenylacetaldehyde, respectively. If J9 and Jl20° are assumed to be

of the same sign, then Jl20° would be equal to or greater than 2.96,
2.76, 2.74, 2.92, and 2.48 Hz, respectively. These results are
unreasonable, since J9 and 01200 are expected to have similar values
(32,38). Since Jg for all these compounds is certainly less than 1 Hz,
the discrepancy between J9 and Jl20° is even greater than that calculated
using the minimum values of the observed coupling constants. If J9

and J1200 are assumed to be of opposite sign, the discrepancy is larger

than if the coupling constants are assumed to have the same sign.

8. The Effect of Solvent Polarity on Rotamer Stabilities

 

The increase in the rotamer ratio 5/5 for phenylacetaldehyde with
increasing solvent dielectric constant, as reflected in the populations

given in Table XV, is logical in light of the higher dipole moment of 5

 

42
relative to 4 (illustrated by I) and 12).

H O O

\ //z‘ x //x
()3 \ if) \

In the case of p;methylphenylacetaldehyde, the dipoles may be
represented as in 14. It is apparent that the dipoles, other than the

carbonyl, should almost completely cancel. If, therefore, overall

H‘ ’3.

\

It
/
H

H

(7.;
54>
I

dipole-dipole interactions are important in determining rotamer
stability, then the rotamer populations of 4 and 5 should remain
constant for pfmethylphenylacetaldehyde regardless of solvent dielectric
constant. This is not the case. The populations of 4 and 5 (and the
free energy and enthalpy differences) are roughly equivalent to

and change in the same manner as those of phenylacetaldehyde, supporting
the idea that only local dipole-dipole interactions are important in

determining rotamer stability.

43

In pfmethoxyphenylacetaldehyde, the overall dipole will depend on
the relative importance of the charge separated resonance form, 16, to
15. Taft and coworkers (39) have taken Op values for the ionization
of benzoic acids and the rate of saponification of benzoate esters and

estima: ed the contributions of GI, the contribution due to induction,

H3C Q13}, fly
xx HBC: o X.

N //z x //f
A \ xl \

H H l5 H H H 16 H
and OR’ the contribution due to resonance. Taft's values of CI and
OR indicate that the methoxy group withdraws electrons by induction
and donates electrons by resonance, the resonance contribution being
about twice as large as the inductive. Comparison of the dipole
moments for anisole, l.l6 D (40), chlorobenzene, 1.52 0 (4l), bromo-
benzene, l.51 D (42), p;chloroanisole, 2.24 D (43), and pfbromoanisole,
2.23 D (44) also indicates that the dipole arising from the methoxy group
is directed towards the phenyl group. This would indicate that
rotamer 4 has a higher overall dipole moment than 5 in pfmethoxyphenyl-
acetaldehyde; consequently 4 should increase in stability relative to
5 in going to solvents of higher dielectric constant if overall dipole-
dipole interactions are important. This is not the case; rather, the
observed trends for rotamer populations, free energy differences, and
enthalpy differences are similar to those of phenylacetaldehyde. This
again implies that local dipole-dipole interactions are important in

determining rotamer stability.

 

44
In the case of pfchlorophenylacetaldehyde, two resonance forms,

I} and 18, are again possible. Taft's 01 and ”R values (39) indicate

K my
K //9 R X}
A \ xi \

H H M H H H 4% H

that the inductive withdrawal of electrons is about twice as important
as the resonance effect. Comparison of the dipole moments for chloro-
benzene, l.52 0 (4l), nitrobenzene, 3.84 D (45), toluene, 0.4 0 (4l),
p;chloronitrobenzene, 2.55 D (40), and pfchlorotoluene, l.74 D (46)
shows that the dipole due to the chloro group is directed away from
the phenyl group. It would be predicted, if overall dipole moment
were important, that the percentage of 5 for pfchlorophenylacetaldehyde
should be greater than for phenyl-, pfmethylphenyl-, or prmethoxy-
phenylacetaldehyde in solvents of high dielectric constant. This is
not the case. The populations, free energy differences, and enthalpy
differences are again similar to those of phenylacetaldehyde. These
results are again consistent with local dipole-dipole interactions
being the major factor determining rotamer stability.

The important dipoles for 2,6-dichlorophenylacetaldehyde are
shown in IQ. If the overall dipole moment were important, then in
solvents of high dielectric constant, rotamer 5 should be less stable

for the dichloro compound than for phenylacetaldehyde. This is not the

 

45
case. In proceeding from nonpolar to polar solvents, the change in

populations is about the same as for phenylacetaldehyde. If the
populations for 4 and 5 are similar to those calculated using 2.40 Hz
as the temperature independent value of the coupling constant, then

the larger p0pulation of 5 for 2,6-dichlorOphenylacetaldehyde to that
of phenylacetaldehyde must be explained by some other factor than

local dipole—dipole interactions. Such a factor could be an attractive
interaction between chlorine and oxygen. In any event, the overall
dipole-dipole interactions cannot be of major importance.

The results for phenylmercaptoacetaldehyde may be compared to those
previously obtained for methylmercaptoacetaldehyde (30). It is found
that the magnitude and trends in rotamer populations, free energy
differences, and enthalpy differences are the same. This may be due
to the dominance of local dipole-dipole interactions or due to the
steric effect of sulfur. If, however, overall dipole-dipole interactions
were of major importance, some difference between the phenylmercapto-
and methylmercaptoacetaldehyde would have been expected due to the
polarizability of sulfur.

The above results and discussion indicate that local dipole-dipole
interactions are important in determining rotamer stability, while

overall dipole-dipole interactions are of minor importance.

46

A close examination of the data in Table VI shows that the coupling
constant of 2,6-dichlor0phenylacetaldehyde decreases in going to
solvents of higher dielectric constant, but for the more bulky
polar solvents within the series (chloroform, methylene bromide, and
methylene chloride) an increase in the coupling constant may be due to
a coordination of the bulky solvent, S, as in 55, which would

destabilize rotamer 5 due to steric interactions with the chlorines.

Cl 0

{ms l/f
/’ \

20

mm
In comparing the AH° and AG° values, it should be remembered

that AH° in high dielectric constant solvents may be overly negative,

since the dielectric constant of the solvent decreases as the

temperature increases. This decrease in the dielectric constant

causes a decrease in the rotamer ratio, 5/5, and results in the calculation

of more negative AH° values. For this reason, in solvents of high

dielectric constant, AG° values generally reflect the enthalpy difference

to a better degree than do the AH° values themselves. This change in

dielectric constant with temperature becomes a severe problem in

systems where rotamer dipole moments differ greatly. In the aldehydes

studied, however, AG° and AH° are usually the same within experimental

error indicating that AS° is probably zero. For p7chlorophenylacetaldehyde

there is a discrepancy between 66° and AH°, indicating that AS° may

 

47
not be zero. The AG° and AH° values calculated for 2,6-dichlorophenyl-

acetaldehyde, using l.35 Hz as the temperature independent value of the
coupling constant, indicate that AS° may be close to zero for solvents
of low dielectric constant, but not so for those of high dielectric
constant. Using 2.40 Hz gives AG° and AH° values of roughly the same
value, indicating that AS° may be nearly zero in all solvents if

this temperature independent value is valid.

C. Chemical Shifts

 

The chemical shift data for the substituted phenylacetaldehydes
may be interpreted best by using model 1 (36) rather than model 5 (35).
Model 5 would predict that Ha in 55 would be deshielded in the plane

H 0

\. //
x \

H H

of the carbonyl group, while 7 would predict it to be shielded. From
Table VIII, it can be seen that for nonaromatic solvents, the chemical
shifts of the methylenic protons move upfield as the dielectric
constant of the solvent decreases. Therefore, these protons are being
shielded to a greater extent than in solvents of high dielectric
constant. The previous results on rotamer stability show that for the
substituted phenylacetaldehydes the stability of rotamer g is increased
as the solvent dielectric constant is decreased. Therefore, the

methylenic protons are being shielded as predicted by model Z. The

48

same arguments may be applied to the chemical shifts of phenylmercapto-
acetaldehyde.

The temperature dependence of the chemical shifts of the aldehydic
and methylenic protons for the substituted phenylacetaldehydes are
given in Tables IX, X, XI, XII, and XIII. It is seen that as the
population of rotamer 5 increases, the chemical shifts of the methylenic
protons move upfield, a fact that is consistent with model Z. The
aldehydic protons for phenylacetaldehyde, pfmethylphenylacetaldehyde,
and p;methoxyphenylacetaldehyde were deshielded with increasing temperature
in all the solvents studied. The chemical shift of the aldehydic
proton for p;chlorophenylacetaldehyde was deshielded in solvents of low
dielectric constant and remained relatively constant in solvents of
high dielectric constant with increasing temperature. The aldehydic
proton in 2,6-dichloroacetaldehyde was shielded with increasing
temperature in all solvents studied. The reasons for this behavior of
the aldehydic protons is not presently understood.

The temperature dependence of the chemical shifts for the aldehydic
and methylenic protons for phenylmercaptoacetaldehyde are given in
Table XIV. The chemical shift of the methylenic protons in most
solvents was constant. In N,N-dimethylformamide and benzonitrile,
the methylenic protons are deshielded with increasing population of
rotamer 5. This may be due to specific solvent solute interactions.
The aldehydic proton was deshielded with increasing temperature in less

polar solvents and was constant in polar solvents.

 

EXPERIMENTAL

A. Reagents and Compounds

All aldehydes were purified either by distillation or by isolation
of the bisulfite addition product. Phenylacetaldehyde, pfmethylbenzyl
cyanide, 2-methyl-2,4-pentanediol, pfmethoxystyrene, pfchlorostyrene,
2,6-dichlorostyrene, chloroacetaldehyde diethyl acetal, and benzenethiol

were obtained commercially (Aldrich Chemical Co.).

B. Solvents
All solvents used in these studies were purified by standard
methods (47). The purified solvents were stored over molecular sieves

in glass stoppered bottles.

C. Synthesis
I. prethylphenylacetaldehyde

 

prethylphenylacetaldehyde was prepared from pymethylbenzyl cyanide
by combining the procedures of Tillmanns and Ritter (48) and Meyers,
gt_gl, (49). To 90 g of concentrated sulfuric acid cooled in an ice
bath, was added 25 g of pfmethylbenzyl cyanide (0.l9 mole) with stirring
over a period of 0.5 hours, followed by 2l.3 g of 2-methyl-2,4-
pentanediol (0.l8 mole) added over a two hour period. This mixture was
poured over l80 g of ice, half-neutralized with 40% sodium hydroxide
solution and extracted three times with l00 ml of chloroform. The pH
was then adjusted to l0 and the product was extracted with ethyl ether
and dried over anhydrous potassium carbonate. After evaporation of the

49

 

50
ether extracts, 8.5 g of 2-(p;methylbenzyl)-4,4,6-trimethyl-5,6-
dihydro-l,3(4H)-oxazine (l9.6%) was obtained as a yellow oil which
solidified on distillation (84-900 at 0.3 mm). The product was
dissolved in a mixture of 200 ml of tetrahydrofuran and 200 ml of
95% ethanol, cooled to -40° and 9N HCl and sodium borohydride solution
(7.6 g, in l5 ml of water containing 2 dr0ps of 40% sodium hydroxide)
were added alternately, keeping the pH between 6 and 8. The reaction
mixture was cooled for an additional two hours, 200 ml of water was
added and the solution was made basic with 40% sodium hydroxide. The
layers were separated and the aqueous layer extracted twice with ethyl
ether. The combined organic layers were washed twice with 200 ml of
saturated sodium chloride solution and dried over anhydrous potassium
carbonate. After evaporation of the solvent, the crude 2-(pfmethylbenzyl)-
4,4,6-trimethyltetrahydro-l,3-oxazine was added dr0pwise to 300 ml
of water containing TOO g of oxalic acid. The produced aldehyde was
steam distilled under a helium atmOSphere. The distillate was saturated
with sodium chloride and extracted three times with l50 ml portions
0f pentane. Distillation 0f the dried pentane extracts yielded 1.6 g of

pure prmethylphenylacetaldehyde (0.0ll mole, 6.6%, 44-46° at 0.5 mm).

11. prethoxyphenylacetaldehyde

 

p:Methoxyphenylacetaldehyde was prepared from prmethoxystyrene by
the procedure of Mannich and Jacobsohn (50). To a suspension of 22 g
of yellow mercuric oxide in a solution of l0 9 of pfmethoxystyrene
(0.74 mole), l00 ml of ethyl ether and l0 ml of water, was added small
portions of iodine (25 9) over a period of one hour. The solution was
filtered and washed twice with saturated sodium thiosulfate solution.
The solution was diluted with 50 ml of ethanol. After the removal of

ether and addition of 100 ml of saturated sodium bisulfite, the solution

5l

was stirred for one hour and the bisulfite adduct was filtered and
washed with ethyl ether. After addition of l00 ml of saturated sodium
bicarbonate to an aqueous solution of the adduct, the solution was
stirred for one hour at 0° and then extracted with ethyl ether, dried
over anhydrous sodium sulfate and evaporated to give 3.9 g of

pfmethoxyphenylacetaldehyde (0.026 mole, 35%).

III. pyChlorOphenylacetaldehyde

 

p;Chlor0phenylacetaldehyde was prepared from pfchlorostyrene by
the procedure of Freeman gt_al, (5l,52,53). To l0 9 (0.0725 mole) of
freshly distilled pfchlorostyrene dissolved in 250 ml of methylene
chloride and cooled to 0° was added dropwise l2.6 g (6.6 ml, 0.082 mole)
of freshly distilled chromyl chloride dissolved in l25 ml of methylene
chloride. After one hour, 6.l0 g (0.094 mole) of zinc dust was added.
It was followed, after an additional l5 minutes of stirring,by 37 ml of
water and l5 9 of ice. The mixture was allowed to reach room temperature
and then steam distilled until 5 2 of distillate were collected. The
distillate was extracted with an equal volume of methylene chloride,
the organic layer was dried over anhydrous magnesium sulfate, decanted,
and the solvent evaporated. The resulting oil was distilled, yielding
0.485;(0.003l mole, 4.3%) of pfchlorOphenylacetaldehyde (colorless
solid, bp 75-78 at 0.6 mm).

IV. 2,6—0ichloroghenylacetaldehyde

 

2,6-Dichlorophenylacetaldehyde was prepared from 2,6-dichloro-
styrene by the procedure of Freeman gt_al, (5l,52,53). To a stirred
mixture of l0.30 g (0.059 mole) of freshly distilled 2,6-dichlorostyrene
in 200 ml of methylene chloride and cooled to 0° was added dropwise

10.32 g (5.4 ml, 0.067 mole) of freshly distilled chromyl chloride

 

52

dissolved in l00 ml of methylene chloride. An hour later, 5 g

(0.077 mole) of zinc dust was added, followed, after an additional

l5 minutes of stirring, by 30 ml of water and l2 9 of ice. The mixture
was allowed to reach room temperature and then steam distilled until

5 2 of distillate were collected. The distillate was extracted with an
equal volume of methylene chloride, the organic layer was dried over
anhydrous magnesium sulfate, decanted, and the solvent evaporated. The
resulting oil was distilled, yielding l.45 9 (0.0077 mole, l2.9%) of
2,6-dichlorOphenylacetaldehyde (colorless solid, bp 95-98° at 0.2 mm).

 

V. Phenylmercaptoacetaldehyde

Phenylmercaptoacetaldehyde was prepared from benzenethiol and
chloroacetaldehyde diethyl acetal by the procedure of Nick, gt_al, (54).
To a solution of sodium phenylmercaptide (ll.0 g, 0.48 mole, of sodium,
l20 ml of ethanol, 58.3 g, 0.53 mole, of benzenethiol) chilled in an
ice bath was added dropwise 39.65 g (0.26 mole) of chloroacetaldehyde
diethyl acetal. After warming, the mixture was heated at 50-60° for
one hour, and was then allowed to stand at room temperature overnight.
The resulting orange solution containing a white solid was filtered,and
the filtrate was diluted with water to twice its volume and extracted
with ether. The ether layer was dried with anhydrous magnesium sulfate.
After evaporation of the ether and vacuum distillation of the residue
32.l6 g of phenylmercaptoacetaldehyde diethyl acetal (0.l4 mole,

54.2%, l3l-35° at 3.4 mm) was obtained.

A mixture of 22.6 g (O.l mole) of phenylmercaptoacetaldehyde
diethyl acetal and l20 ml of l0% sulfuric acid was refluxed at 80° for
45 minutes. The mixture was then steam distilled and the distillate

extracted with ether. The ether layer was dried with anhydrous magnesium

53

sulfate and the ether evaporated. Vacuum distillation gave 5.45 g of

phenylmercaptoacetaldehyde (0.036 mole, 36.0%, 108-110° at 3.7 mm).

D. N.M.R. Spectra

 

The Nuclear Magnetic Resonance spectra were obtained at 60 MHz on
a Varian Associates Model A56/6OD Analytical Spectrometer (Varian
Associates, Palo Alto, Calif.). Samples, in concentrations of
5% vol./vol. for liquids or wt./wt. for solids, were run with tetra-
methylsilane (TMS) as the internal standard. Coupling constants (J)

were recorded at a sweep width of 50 Hz. The recorded coupling constants

 

were averages of six to ten measurements and were calibrated against
known values of acetaldehyde (26,37). Chemical shifts were obtained
at a sweep width of 1000 Hz and were calibrated against a known sample
of tetramethylsilane (0.0 Hz), l,l,l-trichloroethane (164.0 Hz),
dioxane (217.0 Hz), methylene chloride (318.0 Hz), and chloroform
(439.8 Hz). Temperature studies were carried out by using a Varian
Associates V-6040 Variable Temperature controller with a precision of

12°.

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