A STUDY OF MOLECULAR STRUCTURE ‘

ANO INTERNAL ROTATION IN AMIDES

.BY NUCLEAR MAGNETIC RESONANCE f .
SPECTROSCOPY . * ‘

Thesis for the Degree Of Ph. D.

MICHIGAN STATE UNIVERSITY

LESTER REINHARDT ISBRANDT
1972

THE-9’9

This is to certify that the

thesis entitled

A STUDY OF MOLECULAR STRUCTURE
AND INTERNAL ROTATION IN AMIDES
BY NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

presented by
LESTER REINHARDT ISBRANDT

has been accepted towards fulfillment
of the requirements for

PH.D. degree in CHEMISTRY

Date /,” 12—" 7147

0-7639

     
     

  

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ABSTRACT
A STUDY OF MOLECULAR STRUCTURE
AND INTERNAL ROTATION IN AMIDES
BY NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY
BY

Lester Reinhardt Isbrandt

High-resolution nuclear magnetic resonance (NMR) methods have been
employed in a series of studies of molecular structure and internal mo-
tions in amides. A Varian HA-IOO NMR spectrometer was used to obtain
both proton and carbon-13 spectra.

Activation parameters for internal rotation about the central C-N
bond in six previously studied N,N-dimethy1amides, RCON(CH3)2 (R=H,D,
-CH3,-CH2CH3,C1,C013), have been redetermined from proton NMR spectra
by total lineshape analysis. The NMR method for carrying out the analy-
sis has been improved by the digitization of the experimental spectra
followed by computer curve fitting of the lineshapes to the theoretical
lineshape equation containing all the NMR parameters as adjustable vari-
ables. The agreement between the activation parameters determined in
this study and the literature values obtained by total lineshape analy-
sis is quite good and establishes the reliability of the method.

Internal rotation about the central C-N bond in a series of four
unsymmetrically N,N-disubstituted amides, CH3CON(CH3)R (R=ethyl, iso-
propyl, Efbutyl, and cyclohexyl), have been obtained by the proton NMR
total lineshape technique developed for the study of the N,N-dimethyl-

amides. Steric effects appear to be of particular importance and larger

Lester Reinhardt Isbrandt

groups, whether substituted on carbon or nitrogen, consistently reduce
the rotational barrier.

Application of lanthanide shift reagents has been proven to be a
reliable method of assigning the NMR resonances, proton or carbon-13, to
substituents on the gi§_and Egggg_rotational isomers of disubstituted
amides. Assignments have been made in the proton NMR spectra for a rep-
resentative series of amides and in the carbon-l3 NMR spectrum of N,N—di-
gyprOpylformamide.

The carbon-l3 NMR chemical shifts of fifty monosubstituted and di-
substituted amides have been measured. Assignments have been made by the
use of model systems and the application of lanthanide shift reagents.
The chemical shift difference between carbon atoms of groups £i§_and
£5325 to carbonyl oxygen in disubstituted amides is greatest for thecx-
carbon, 22, 5.1 ppm in formamides and ca, 3.5 ppm in alkylamides, and

decreases for carbons farther away from the carbonyl group.

A STUDY OF MOLECULAR STRUCTURE
AND INTERNAL ROTATION IN AMIDES
BY NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

BY

Lester Reinhardt Isbrandt

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1972

To Pamie

ACKNOWLEDGEMENTS

The author would like to express sincere appreciation to Professor
Mex T. Rogers for his guidance, encouragement, and patience during the
course of this study.

The financial support of the Dow Chemical Company, the National
Science Foundation, and the Chemistry Department during the various parts
of this study are gratefully acknowledged.

To Pamela, my wife, whose ever-present smile, encouragement, and
self-sacrifice enabled me to complete this phase of my education, I offer

my deepest appreciation.

TABLE OF CONTENTS

Page
INTRODUCTION ..... ............. . .............. . .................... l
HISTORICAL ........ ................. . .......... .... .......... . ..... 3
Determination of Barriers in Amides . .................... ..... 4
Assignments of Resonances in Amides ..... ................ ..... 8
Application of Carbon-13 NMR Spectroscopy to Amides .... ...... 9
Additivity of Carbon-13 Chemical Shifts ............ .......... 11
THEORETICAL . ................. .......... ........ . .................. 14
Introduction ................................................ 14
Spin-Spin and Spin-Lattice Relaxation ................. . ...... 15
NMR Lineshape Theory ..... .. ..... ........................ ... 16
The Lineshape Equation with Exchange ......................... 19
Activation Parameters ............... ........................ . 22
Chemical Shifts ........... . .............. .... ................ 23
Nuclear Spin-Spin Coupling ..... .................... ..... ..... 25
Proton Decoupling .... ...... . .... .......... . ................. 27
Nuclear Overhauser Enhancement .......... . .................... 28
Lanthanide Induced Chemical Shifts ........................... 32
EXPERIMENTAL ...................................................... 34
Preparation of Compounds ..................... ... ..... . ...... 34
Physical Constants of Compounds Studied ................. ..... 35
Spectrometer ................................................ 40
Time Averaging and Digitization of Spectra ................... 43
Sample Preparation .. ..... .... ..... ... ................... 43
Bulk Diamagnetic Susceptibility Corrections .......... . ....... 45
Determination of Energy Barriers of Hindered
Internal Rotations ......................................... 46
RESULTS . ................................... . ..................... . 48
Hindered Internal Rotation in Tertiary Amides ................ 48
Symetrically Disubstituted Amides ......................... 48
N,N-Dimethy1acetamide ............ . ..................... 48
N,N-Dimethylcarbamylchloride ........................... 55
N,N-Dimethylformamide .................................. 55
N,N-Dimethylformamide-d1 ..... . ......................... 55
N,N-Dimethylpropionamide ...... ...... . .................. 62
N,N-Dimethyltrichloroacetamide ......................... 62

TABLE OF CONTENTS - Continued

Page
Unsymmetrically Disubstituted Amides ................. . ..... 62
N-Ethyl-N-methylacetamide ............ ......... . ....... . 62
N-nfButyl-N-methylacetamide ............................ 62
N-Cyclohexyl-N-methylacetamide ............. ............ 62
N-Isopropyl-N-methylacetamide ... ....................... 73
Resonance Assignments in the Proton NMR Spectra of
Several Tertiary Amides . ....... .......... ....... ... ........ 73
l-Methyl-Z-pyrrolidinone .................... . .......... 73
N,N-Dimethylformamide ................ . ................. 78
N,N-Diethylformamide ................................... 78
N ,N-Diisopropylformemide ............................ ... 82
N,N- Dimethylacetamide .... ............................. 82
N,N- -Dimethy1carbamylchloride .............. ...... ....... 86
N ,N-Dimethyltrichloroacetamide .................. . ...... 86
N,N-Dimethyltrifluoroacetamide ..... . ................... 86
Ethyl-N,N-dimethylcarbamate ............ ......... . ...... 86
N-Isopropyl-N-methylformamide .......................... 91
Carbon-l3 Chemical Shifts of Aliphatic Amides ................ 91
Monosubstituted Amides ................................. 93
Symmetrically Disubstituted Amides ..................... 9S
Unsymmetrically Disubstituted Amides ................... 100
DISCUSSION ......... ..... . ......... . ..... . ............ .... ......... 103
Hindered Internal Rotation ...... ............................. 103
Total Lineshape Analysis ..... .............................. 103
The Frequency Factor in the Arrhenius Equation .. .......... . 104
Rotational Barriers in N,N-Disubstituted Amides ........... . 105
Resonance Assignments in Tertiary Amides by
Lanthanide-induced Shifts .................................. lll
Carbon-13 Chemical Sh1fts of Am1des .......................... 115
SUMMARY .. .................................................... 119
LIST OF REFERENCES ....... . ....... . . ............... . ............. 120

ii

LIST OF TABLES

TABLE Page

1. Reported activation parameters for hindered rotation

in N,N-dimethylformamide ..................... ...... . ......... 5
2. Reported activation parameters for hindered rotation in

some other dimethylamides ........................ .......... .. 7
3. Substituent parameters correlating alkane carbon-13

chemical shifts in ppm ...... ....... ............. .... ....... .. 12
4. Shielding effects of some common substituents in aliphatic

systems ...... ............ .... .................... . ........... l3
5. N-monosubstituted amides studied ........................... .. 36
6. N,N-Dimethylamides studied .................. . ................ 37
7. Other symmetrically N,N-disubstituted amides studied ......... 38
8. Unsymmetrically N,N-disubstituted amides studied ........... . 39
9. Volume magnetic susceptibilities and bulk magnetic

susceptibility corrections for several compounds ... ....... ... 45
10. Experimental data and calculated activation parameters

for the internal rotation about the central C-N bond in

neat N,N-dimethylacetamide ..... .......... .................... 53
11. Experimental data and calculated activation parameters

for the internal rotation about the central C-N bond in

neat N,N-dimethylcarbamylchloride ............................ 56
12. Experimental data and calculated activation parameters

for the internal rotation about the central C-N bond in

neat N,N-dimethylformamide - Method I ................... ..... 58
13. Experimental data and calculated activation parameters

for the internal rotation about the central C-N bond in

neat N,N-dimethylformamide - Method II ............ ........... 6O
14. Experimental data and calculated activation parameters

for the internal rotation about the central C-N bond in

neat N,N-dimethylformamide-dl ................................ 63

iii

LIST OF TABLES - Continued

TABLE

15.

16.

17.

18.

19.

20.

21.

22.

23.-

24.

25.

26.

Page

Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N’N-dimethYIPropionamide ......OOOOOOOOOOOOOO......I... 65

Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N’N-dimethyltriChloroacetmide O I O O O O O O O O C O O O O O O I O O O O O O 67

Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N-ethYI—N-methYlacetamide coooooooocoo-0000000000000... 69

Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat NfErbuty1-N‘methYIacetamide oooooooooooooooooooooooooon 71

Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N'CYCthBXYl-N-methYIacetaMIde oooooooooooooooooooooooo 74

Experimental data and calculated activation parameters
for the internal rotation about the central C—N bond in
neat N-iSOpr0py1‘N-methy13C8tamide ooooooooooooooooooooooooo 76

Proton chemical shifts, observed and calculated, in 1-
methyl—Z-pyrrolidinone with increasing amounts of
Eu(f0d)3 0.00.0................0............OOOOOOOOOOOOOOOO 79

Proton chemical shifts, observed and calculated, in
N,N-dimethylformamide with increasing amounts of
EU(de)3 ......OOOOOOOOOIOOOOOO.....OOIIOIOOOOOCOO0.0.0.0... 8O

Proton chemical shifts, observed and calculated, in

N,N-diethylformamide with increasing amounts of
EU(de)3 0............OOIOOOOOOOO.......OOIOOOOOOOOOOOOOIOO. 81

Proton chemical shifts, observed and calculated, in
N,N-diisopropylformamide with increasing amounts of
Eu(f0d)3 0.0.0.000...0.0.0.0000..............IOOIOOOOOOOOOOO 83

Proton chemical shifts, observed and calculated, in
N,N—dimethylacetamide with increasing amounts of
Eu<f0d)3 ......OOOOOOOOOOOOIOOO.....OOOOOOOOOOOOO0.00.0.0... 84

Proton chemical shifts, observed and calculated, in
N,N-dimethylacetamide with increasing amounts of
Pr<f0d)3 ......OOOCOOO......OOOOOOCOOO......OOCOOOOOO....... 85

iv

LIST OF TABLES - Continued
TABLE Page

27. Proton chemical shifts, observed and calculated, in
N,N-dimethylcarbamylchloride with increasing amounts
Of Eu(f0d)300.000000000000000 00000000000000 oooooooo oooooooo o 87

28. Proton chemical shifts, observed and calculated, in
N,N-dimethyltrichloroacetamide with increasing amounts
Of Eu(fod)300.00.00.00000000000000000... ......... 00 ...... 000 88

29. Proton chemical shifts, observed and calculated, in
N,N-dimethyltrifluoroacetamide with increasing amounts
Of Eu(f0d)3 00000000000.000000000000000000000.000000000 ...... 89

30. Proton chemical shifts, observed and calculated, in
ethyl-N,N-dimethylcarbamate with increasing amounts of
Eu(f0d)3 ....... cocoons-00000000000... ..... o ooooooo o ooooooooo 90

31. Proton chemical shifts, observed and calculated, in
N-isopropyl-N-methylformemide with increasing amounts

0f EU(f°d)aooooo oooooooo oooooooo ..... oooooooooooooooo ooooooo 92
32. Carbon-13 chemical shifts of some Nemonosubstituted

amides. ...... 00000.0...00000000000 ...... 00000000000000.0000. 94
33. Carbon-13 chemical shifts of some N,N-dimethylamides ..... ... 96

34. Carbon-13 chemical shifts of some other symmetrically
N,N-disubstituted amides ....... ............ . ................ 97

35. Assignments of carbon-13 chemical shifts for the N-
alkyl substituents of N,N-difinepropylformamide in carbon
tetraChlorj-de oooooooooo o oooooo o o oooooo o o o o o o o oooooo o o ooooo o o 99

36. Carbon-13 chemical shifts of some unsymmetrically N,N-

disubstituted amides ........ ..... .. ......................... 101
37. Activation parameters for hindered internal rotation

in some symmetrically N,N-disubstituted amides .............. 106
38. Activation parameters for hindered internal rotation

in some unsymmetrically N,N-disubstituted amides ... ......... 107
39. Conformer equilibria in unsymmetrically N,N-disubstituted

amides ..... ...... .................... . .......... . ........... 111
40. AEu values for some N,N-disubstituted amides ................ 113

41. Proton resonance assignments in some N,N-disubstituted
amides 0.000000000000000 OOOOOOOOOOOOOOOO 00000000000000. 000000 114

LIST OF FIGURES

FIGURE Page
1. Resonance in amides .......... .... ............................ 1
2. The amide group and conformers of substituted amides ......... 3

10.

11.

12.

13.

14.

15.

16.

Energy-level diagram for an AX two-spin system in
presence of a magnetic field ....... ...... . ................... 29

Carbon-13 NMR spectrum of N,N-diethylpropionamide ............ 42

Observed (X) and calculated (0) signals of the N-methyl
protons in neat N,N-dimethylacetamide at T = 325.7°K . ........ 49

. Observed (X) and calculated (0) signals of the N-methyl

protons in neat N,N-dimethylacetamide at T = 340.1°K ... ...... 50

. Observed (X) and calculated (0) signals of the N-methyl

protons in neat N,N-dimethylacetamide at T = 343.0°K .. ....... 51

. Observed (X) and calculated (0) signals of the N-methyl

protons in neat N,N-dimethylacetamide at T = 348.5°K ......... 52

Plot of ln(1/27) against 109/T°K for neat N,N-dimethyl-

acetamide ........ .............. . ........... . ................. 54
Plot of 1n(1/21) against 10?/T°K for neat N,N-dimethyl-
carbamylchloride. ....................»....................... 57
Plot of 1n(1/21) against 103/T°K for neat N,N-dimethyl-

formamide - Method I ..... ..................... ..... ... ....... 59
Plot of 1n(1/21) against 103/T°K for neat N,N-dimethyl-

formamide - Method II .. ...... ...... ......... . ................ 61
Plot of 1n(l/Zr) against 10?/T°K for neat N,N-dimethyl-
formamide-dl ............ . ............ ..... ................... 64
Plot of 1n(1/Zr) against 103/T°K for neat N,N-dimethyl-
propionamide ................................................. 66
Plot of 1n(1/21) against 103/T°K for neat N,N-dimethyl-
trichloroacetamide ........................................... 68
Plot of 1n(l/21) against lO?/T°K for neat N-ethyl-N-
methylacetamide .............................................. 70

vi

LIST OF FIGURES - Continued

FIGURE Page
17. Plot of 1n(1/21) against 103/T°K for neat N-n-butyl-N-
mthylacetamlde 0 0 C C C 0 C C O C . C O C O C O O O C 0 0 C C C C O O O O C C C C C C O O O ..... 72
18. Plot of 1n(1/27) against 103/T°K for neat N-cyclohexyl-N-
methylacetamide ...... ............ ... ......................... 75
19. Plot of 1n(1/21) against 103/T°K for neat N-isopropyl-N-
methylacetamide ..... . ....... ...... ..... , ..................... 77

vii

INTRODUCTION

Amides have been studied more extensively by nuclear magnetic reso-
nance (NMR) spectroscopy than nearly any other class of compounds. Sub-
stantial stimulus arises from the importance of amide linkages in peptide
chains and proteins, as well as interest in the electronic structure of
a carbonyl group partially conjugated with a nitrogen lone pair. Most of
the NMR studies are concerned with this partial double-bond character in
the central C-N bond. The double-bond character resulting from a con-
tribution of resonance structure II to the ground state of amides (1)

leads to restricted rotation about the C-N bond.

Figure l. Resonance in amides.

As a result of the nonequivalence, geometrically and magnetically, of the
nitrogen substituents, even when R1 = R2, the NMR spectra provide a great
deal of information about the amide structure. The NMR investigations of
amides have largely involved identification and assignment of conformers,
measurements of scalar coupling constant and chemical shift values and

their interpretation, and study of hindered internal rotation.

l

2

-A comprehensive presentation of the subject including preparations and
molecular properties of amides, may be found in "The Chemistry of Amides",
edited by Zabicky (2).

The research reported in this thesis consists of the following:
(1) re-examination of the proton NMR method for determining rotational
energy barriers of several N,N-dimethylamides by total lineshape
analysis; (2) examination of the rotational energy barriers of a series
of unsymmetrically N,N-disubstituted amides by proton NMR using total
lineshape analysis; (3) assignment of the proton NMR resonances of amides
by the application of lanthanide shift reagents; (4) the investigation
of carbon-13 chemical shifts in a series of N-monosubstituted, symmet-

rically N,N-disubstituted and unsymmetrically N,N-disubstituted amides.

HISTORICAL

The present knowledge of the molecular structure of the amide groupie

o R A o R (A
/, 1( ) §§ ,/ 2 )
C—N
\ /
112(3) R3
III IV

R1(3)

Figure 2. The amide group and conformers of substituted amides.

founded largely upon the results of x-ray and electron diffraction anal-
ysis, while that of the electronic structure is derived from spectro-
scopic experiments (ultraviolet, infrared, nuclear magnetic resonance,
microwave) and the results of various semi-empirical and ab initio quan-
tum mechanical calculations (2).

X-ray structure analyses of a variety of crystalline amides estab-
lished the planarity of the amide framework (3-5). Formamide (6) has
been shown by microwave spectroscopy to have a slightly pyramidal confor-
mation about the nitrogen atom in the gas phase while N,N-dimethylform-
amide is essentially planar (7). However, the pyramidal conformations
will invert very rapidly, so that formamide and simple substituted amides,

even if slightly non-planar, would appear effectively planar in NMR studies.

4

Pauling (1) postulated that the rotation about the central C-N bond
of amides would be restricted due to the partial double-bond character in
this bond. As a result of this double-bond character, the environments
of the nitrogen substituents are not averaged, and should be observed
separately by NMR spectroscopy. This was confirmed by Phillips (8) from
a proton NMR study of N,N-dimethylformamide and N,N-dimethylacetamide.
Gutowsky and Holm (9) developed the first application of NMR signal anal-
ysis to the determination of energy barriers in a study of internal rota-
tion in N,N-dimethylformamide and N,N-dimethylacetamide. They obtained
the rotation rates, 21, as a function of temperature and fit them to an
Arrhenius-type equation, 1/2T = A exp(-Ea/RT), to obtain an energy barrier
E8 and frequency factor A; a single parameter, the apparent peak separa-
tion for the N-methyl peaks, was used.

Woodbrey and Rogers (10,11) followed with an extensive study of
dimethylamides, and were able to correlate the activation energy of the
'barrier with structure. A single parameter, the ratio of maximum to
central minimum in the partially coalesced peaks, was used in the analy-

sis.
Determination of Barriers in Amides

These early investigations were the beginning of numerous examina-
tions and re-examinations of the hindered internal rotation problem in
amides by NMR spectroscopy. Table 1 shows that the barrier for N,N-
dimethylformamide has been determined over and over again, producing ran-
dom numbers between the extremes of 6.3 and 28.2 kcal/mole for the acti-

vation energy, Ea’ and 4.6 and 17.2 for the logarithm of the frequency

5

Table 1. Reported activation parameters for hindered rotation in

N,N-dimethylformamide.

 

 

 

 

 

Ea Log A
Solvent kcal/mole (A = sec-1) Methoda Reference
Hexa°h1°r°' 6.3 i 0.3 4.60 t 0.01 A 32
ethane

Neat 7 i 3 3-7 A 9
“ejigiigiige 9.4 i 1.0 A 33
Neat 9.6 i 1.5 6.5 A,B,C 34
CFCla 11.3 i 2.0 A 33
Neat 15.9 i 2.0 16.8 i 2.0 A 33
Acetone-d5 16.8 i 2.0 A 33
Neat 18.3 i 0.7 10.8 i 0.4 C 11
Neat 18.7 i 0.9 11.8 i 0.6 C 35
CC1A . 20.5 i 0.2 12.7 i 0.5 D 25
Neat 22.0 13 A,B,Cb 36
Neat 26 16 A,B,C 37
Neat 27 .4 16 A,B,Cc 36
Neat 28.2 i 2 17.2 A 38
Formamide ‘ 26.3 i 2.6 15.5 i 1.5 C 35
8A - Peak separation approximation.

B - Line width approximation.

C - Other approximate treatment.

D - Total line-shape analysis.

bSpectra taken at 100 MHz.

cDimethylformamide-dl.

6
factor, log A. It was shown (12) that all the approximate NMR methods
tended to introduce systematic errors into the values of the rotational
barriers, and the results of Table 1 dramatize the shortcomings of apply-
ing approximate formulas and single-parameter methods. The entire subject
of the barrier to rotation in amides has been reviewed extensively by
Johnson (13), Binsch (14), Stewart and Siddall (15,16), Kessler (l7),
and Lowe (18). The conclusion drawn by these authors is that the best
method for the determination of energy barriers in amides is by total
lineshape analysis and all other methods must be viewed with suspicion.
In the total lineshape method, the experimental spectrum is compared
point by point with the theoretical spectrum calculated from modified
Bloch equations; the rotation rate 1, chemical shift in the absence of
exchange 8v, fractions of conformers pA, p3, and linewidths in the ab-
sence of exchange T2A’ T23, are taken to be adjustable parameters and a
computer method employed to obtain best values of each of them from the
data. These authors point out that extreme care is required in measuring
the high-resolution NMR spectrum at each temperature. The radiofrequency
field must be set well below saturation, the sweep rate must be extremely
slow to insure minimal distortion in the lineshape, and the temperature
at which the spectrum is recorded must be very stable. If these measures
are not taken into account, the recorded lineshapes will be non-Lorentzian
and curve-fitting to the theoretically calculated lineshape will lead to
erroneous NMR parameters. Total lineshape analysis has now been used by
several research groups (19-31) for the determination of barriers in
various amides and the activation parameters which have been reported for
the amides that have been re-examined in this research are listed in

Table 2.

.AMNV nee a-0 «sausage» .NN «wee com

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.vonuoa osuouaamm an woumama<u

.eaoo 6% N 0H08 0.0Hn

.nvuopaamuoomamnuoaaauz.Zm

 

on
em
can
AH

am
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van
Ha

mHH
mm
HH

mHH
me
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mm
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HA

m.0

BOO

I
NNNH

+l +I +l H

H

H

h-+l
N
F4

 

monouomom

H.0 H H.mH

UNO‘lfil-fi
COCO
Fir-IF!

+I +| +I +I

memo
\OMON

H.0 H 0.0a H.0

¢.o~

H.0 H m.wa H.o

 

mHoa\Hmox

NEG

mHoa\Hmox
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QQ

Nfi'
COM
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Firs
0‘0:

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00
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PIE-I

“10¢
COO

+l +I +I

 

mulumm N 4%

4 won

 

0.0 H 0.0a
H.0 H n.ma
0.0 a 0.0a
«.0 A m.m meeaeueeeouoaeeeuuaaeueaaotz.z
H 0.5a
m.0 H 0.0a
0.0 H 0.0a
m.o A m.~ weeuoaeuaaaeeueuaaeumeeouz.z
H.0 a 0.0a
0.HN
5.0 H «.0 owaamaowaoumahsuoaanlz.z
H.o a o.mH
0N
0.0a
o.ma
N.0N
0.mN
N H NH
«.0 H 0.0a unassumomaanuoafinlz.z
oaoa\amox venomaoo
m
m

 

.moeeaeaasuuaae

nonuo oaom dd aoHuMuou wouovawn now pneumamumm aowum>wuom vouuomom

.N OHAMH

8

Although symmetrically N,N-disubstituted amides have been rather
intensively investigated, relatively few measurements have been made on
unsymmetrically substituted compounds. Rotational barriers in three
formamides, HCON(CH3)R[R = mCH2-, 02CH- and mC(CH3)H-] were determined by
Franconi (41) who found no significant difference among the three within
the rather large errors involved. Gehring 35 a1. (38) reported activa-
tion parameters for five compounds and showed that a large decrease in
the barrier occurs when one of the substituents is the vinyl group.
Gutowsky st 31. (29) made a study of N-methyl-N-benzylformamide, Weil
_e_§ 31. (42) of N-methyl-N-picrylacetamide, and Mannschreck et al. (43,44)

of N-mesityl substituted amides.
Assignment of Resonances in Tertiary Amides

Except in a few cases where there is chemical shift degeneracy, the
‘gig (to oxygen) and the £5333 substituents on nitrogen give well separ-
ated NMR signals whenever rotation around the C-N bond is slow on the NMR
time scale. The principal cause of the chemical shift between the gig
and trans NMR signals is the anisotropy of the magnetic susceptibility of
the amide grouping (46). The chemical shift is observed whether substi-
tution on the nitrogen atom is symmetrical or unsymmetrical. Assignment
of the observed resonances to protons at sites A,B has been of consider-
able interest and is particularly important in the case of unsymmetrical
substitution, when it serves to identify the isomers, III and IV (Figure
2). Also, the values of the proton chemical shifts for groups gig or
‘Egggg to oxygen yield information on the structure of the amide molecule,
as well as the nature of the adducts and complexes that it forms with

other molecules.

9
Several criteria have been used to identify the proton resonances

for R1 and R2 as gig or 5533;. These include: (a) inequality of the gig
and 55225 coupling constants (47) for the protons of R3 with those of R1
and R2, (b) differential solvent shifts in an aromatic solvent (48,49),
(c) the nuclear Overhauser effect (50,51), and (d) contact shifts induced
by complex formation with paramagnetic metal ions (124). Most of these
methods are quite limited in scope of application and the assignments may

not be unequivocal (51), particularly when R3,R1,R2 are larger groups.
Application of Carbon-13 NMR Spectroscopy to Amides

Very limited attention has been given to the carbon-13 NMR spectros-
copy of amides compared to proton NMR since the low natural abundance
(1.1%) of the carbon-13 isotope and the reduced magnetogyric ratio
(7C/7N = 0.251) combine to greatly reduce the detectability of the
carbon-13 NMR signal. The signal-to-noise ratio may be significantly
enhanced with proton decoupling techniques, increased sample size, and
utilization of time-averaging techniques. The instrumentation necessary
for, and chemical applications of, carbon-l3 NMR spectroscopy have been
recently discussed by Stothers (52) and by Randall (53).

The first reported observation of the carbon-13 resonance in amides
was made by Lauterbur (54), who observed the carbon-13 chemical shifts in
N,N-dimethylformamide. McFarlane (55) reported the carbon-13 chemical
shift difference between N-methyl carbons in N,N-dimethylformamide, N,N-
dimethylacetamide, and N,N-dimethylcarbamylchloride in five different
solvents of various dielectric strengths. The chemical shift differences

were invariant to the choice of solvent. He pointed out that the

lO
principal contribution to the carbon-13 chemical shift differences be-
tween the Ndmethyl carbons in these amides arises from an intramolecular
electric field. This field will also affect the proton chemical shifts,
although to a smaller extent, since it is the paramagnetic contribution
to the shielding which is involved.

Levy and Nelson (56) studied the spin-lattice relaxation times in
N,N-dimethylformamide, N,N-difig-butylformamide, and N,N-di-Efbutylaceta-
mide by carbon-13 Fourier transform NMR spectroscopy. They found sig-
nificant carbon steric compression shifts for the four aliphatic carbons
£5223 to the formyl hydrogen and eclipsing the carbonyl oxygen in N,N-di-
‘g-butylformamide. These steric shifts range from over 5 ppm for the
a-carbon to ca: 0.1 ppm for the 8-carbon on the same chain. Carbon spin-
lattice relaxation behavior in N,N-dijg-butylformamide indicated that the
ends of both butyl chains have significantly increased motional freedom.

Gansow, Killough, and Burke (31) studied hindered internal rotation
in N,N-dimethyltrichloroacetamide by carbon-13 NMR spectroscopy. Their
results are comparable to the best activation parameters by proton NMR.
However, they pointed out several experimental shortcomings of the tech—
nique. First, the reported spectra were the absolute limit of the carbon-
13 NMR sensitivity and several thousand scans were necessary. Second,
as lines broaden or as measurements are performed at higher temperature,
sensitivity drops dramatically for two reasons: (a) Boltzmann popula-
tions readjust,and (b) as a result of the large low-temperature chemical
shift difference, broadening and coalescence occur over a large spectral

area.

ll

Additivity of Carbon-13 Chemical Shifts

Grant and Paul (57) found that alkanes absorb over a range of approx-
imately 45 ppm and also discovered that the chemical shifts could be des-
cribed by the relation

1

5c =B+JgAjnllj , (1)

where 8: is the ith carbon-13 shift, A an additive shift parameter for

J

the jth position, n is the number of atoms in the jth positions, and

1)
B is a constant. For linear alkanes five parameters (Aj) correlate 30
shifts ranging over 37 ppm, with a standard deviation (0) of 0.2 ppm.

For the branched alkanes additional parameters are required to account
for the shieldings of highly substituted carbons and their immediate
neighbors. With a total of 13 parameters, 53 measured chemical shifts
are correlated with o = 0.3 ppm. Five of these parameters, labeled<2, B,
7, 8, and 5 factors, represent the effect of replacing a hydrogen atom

in the indicated position with a methyl group while the remainder account
for the effects of branching; for example, a factor for methyl carbons
bonded to a tertiary carbon is denoted 1°(3°). These substituent param-
eters are listed in Table 3. The constant B has the value -2.5 ppm. To

illustrate the manner in which these parameters may be employed, consider

C-2 of 3-methy1pentane for which 8c is given by [B +IZa + 20 + 7 + 2°(3°)]

OBS

= 29.5 ppm, while 5c

= 29.3 ppm (57).
Several families of substituted hydrocarbons have been examined by
this empirical method and the general trends follow those found for

hydrocarbons, with the additional feature that polar substituents exhibit

12

Table 3. Substituent parameters correlating alkane
carbon-13 chemical shiftsa in ppmb.

 

a 9.1 i 0.1 1°(3°) -1.1 i 0.2
s 9.4 2 0.1 1°(4°) -3.4 i 0.4
7 -2.5 x 0.1 2°(3°) -2.5 i 0.2
5 0.3 i 0.1 3°(2°) -3.7 i 0.2
e 0.1 i 0.1 4°(1°) -1.5 1 0.1

 

8Reference 57

bIn this and the following Table, a positive value indicates a shift to

low field. Values from single observations: 2°(4°), -7.2; 3°(3°), -9.5;
4°(2°), -8.4. Symbols are defined in the text.
rather larger inductive deshielding effects at the immediate neighbors
(i.e., theIJ and 8 effects) while the 7 effects are comparable to those
of methyl groups. To illustrate the effects produced by a selection of
substituents, some representative results are given in Table 4 most of
which were obtained from the data for l-substituted alkanes.

Perhaps the most distinctive feature of these substituent parameters
is the change for the effect of a 7-methyl carbon with respect to the<1
and 8 effects. The original proposal by Grant and Paul (57) that the 7
effects are caused by conformational interactions appears to be sound,
since it is generally observed that carbon atoms in sterically congested
environments tend to absorb at higher fields than those in otherwise

comparable orientations.

Table 4.
substituents in aliphatic systems.

13

Shielding effects8 of some common

 

 

bExcluding 2-a1cohols, RCHOHCH

3.

..9L. .Ji_. _JL_ ._§_ .jL. .Bsfgssggg
01 31.2 10.5 -4.6 0.1 0.5 58
Br 20.0 10.6 -3.1 0.1 0.5 58
I -6.0 11.3 -1.0 0.2 1.0 58
NH2 29.3 11.3 -4.6 0.6 0.6 53
. 1° 48.3 10.2 -S.8 0.3 0.1 59
on b
2° 40.8 7.7 -3.7 0.2 0.3 59
coon 20.9 2.5 -2.2 1.0 1.2 60
000' 24.4 4.1 -1.6 1.2 60
RCO 30 1 -2 1 61
aIn ppm.

THEORETICAL
Introduction

Nuclear magnetic resonance is a spectroscopic phenomenon observed

only for nuclei which possess a magnetic moment, it given by
if = 7i“? = VIII/2n . (2)

where 7 is the magnetogyric ratio of the nucleus, S is the angular momen-
tum of the nucleus, h is Planck's constant, I is the nuclear spin vector,
given bygI = I(I+l), and I is the spin quantum number. When the nucleus
is placed in a uniform magnetic field, there are (21+1) energy levels
available, each corresponding to a different component of the angular
momentum with values I, I-l,...—I+l, -I. The absorption or emission of an

appropriate quantum of energy,
AB = hv = 7hHo/2fl = PHD/I 9 (3)

will enable the nucleus to make a transition from one energy level to an
adjacent level.

In order to observe an energy transition the population of the
energy levels must be different. For an ensemble of nuclei the relative

populations are given by the Boltzmann factor

14

15

 

N l m“Ho
ii— : exp[(21+l)mHO/IRT] :: “2'11?“ - m, ) , (4).

where m is the nuclear magnetic quantum number with values I, I-1,...

-I+l, -I, k is the Boltzmann constant, and T is the absolute temperature.
After the nuclei have undergone a transition, some mechanism is required
whereby nuclei in an upper spin state can relax to a lower state so that

the absorption of energy may continue.

Spin-Spin and Spin-Lattice Relaxation

Spin-lattice relaxation is a process by which a nucleus in an upper
spin state may give up energy to the lattice in the form of translational
or rotational energy. Random molecular motions of magnetic nuclei result
in fluctuating magnetic fields, which may have an oscillating component
whose frequency will match the precessional frequency of the magnetic
nuclei in the upper spin state. When the two are in phase, the nucleus
will be able to lose its extra energy to the lattice and drop to a lower
energy level.

The rate that magnetic nuclei of spin I = 1/2 approach their equilib-

rium distribution, no, is given by

3: T1 0 , (5)

where T1 is the spin-lattice relaxation time, and n is the excess popula-
tion of the lower energy state at time t. The magnitude of T1 depends on

the magnetogyric ratio of the nucleus and on the nature of the molecular

l6

motions. The reciprocal of T1 gives an approximate measure of the line
width due to spin-lattice relaxation.

Another type of relaxation is by spin-spin'interaction. The pre-
cession of a magnetic nucleus about the fixed axis of a uniform magnetic
field, fig, may be resolved into a static component parallel to E; and a
rotating component parallel to BL. ‘When the rotating component is at the
correct frequency, there is an exchange of spin energy between two
neighboring nuclei. Spin-spin relaxation thus results in no net change
of spin state. The spin-spin relaxation time is further decreased by the
small variation in the local field at each nucleus due to the fields of
neighboring nuclei. The small local magnetic fields will add to or
subtract from the applied field, fi;, resulting in a larger range of fre-
quencies at which nuclei of the same type will absorb energy.

Rapid rotation and tumbling, as found in most liquids and gases, will

average the local magnetic fields so that T1 and T2 become equivalent.
NMR Lineshape Theory

To describe the time dependent variation of the components of the
total nuclear magnetic moment per unit volume, Bloch used a set of phenom-
enological equations (62). Bloch considers a nucleus with III = (h/Zx)-
TI(I:I) and magnetic moment fi== ngas a tiny gyroscope. The forces it
experiences in an external constant magnetic field in the z direction, E:=
[O,O,HO}, cause it to move in such a way that the rate of change is given

by the torque

0.0.
n Inez
ll
2
2

713x13] . (6)

17
with components

dux/dt = 7lusz - quy] = 71120), (6a)
du/dt = ”“sz - utz] = -7qux (6b)
duz/dt = 701x11), - uny] = 0 (6c)

These equations indicate that the nuclear moment : precesses about the
z-axis with an angular frequency<no = 7H0 in a clockwise fashion. In a
sample containing a large number of identical dipoles, all will precess
with angular frequency'wb, but their phases will be randomly distributed
over a cone about the z-axis. The resultant macroscopic magnetization
will therefore only have a component in the z direction, N; = {0,0,Mb].
If the system is disturbed by a second magnetic field, Ra, rotating
in the xy plane with an angular frequencyem, in the neighborhood of wb,
and in the same sense as the precessional motion of the nuclei so that
R; = {H1 cos cut, -Hl sin wt, 0], then the x and y components of M will be-

come different from zero. The quantitative description is

(if? 2 ~

dt — [Mxfi] , (7)
with E = {H1 cos (0t, -H1 sin wt, 0]. Instead of using the fixed laboratory
coordinate system,iJ:is useful to refer the components of the total mag-
netization to a set of axes rotating about R; with angular frequency a»

In this rotating frame E; is stationary, causing the time dependence of

the right-hand side of Equation (7) to vanish. With E; coinciding with

18

the rotating x-axis, the components become

de/dt = (coo-w)My (7a)
dM/dt = -(a)o-w)Mx+7H1Mz (7b)
sz/dt = ~7H1My . (7c)

Equation (7c) shows that the My magnetization is responsible for a change
in M2 and thus in the net nuclear Zeeman energy of the system. M.y cor-
responds to the absorption mode, and Mg describes the dispersion mode
signal. Both effects can be expressed in a single equation if one defines

the magnetization in the xy plane by the complex quantity
G a: Mx+1My , (8)

so that Equations (7a) and (7b) can be combined to

__ ..- -1(wo-w)c+ 17111142 . (9)

The description of Equations (7) is still incomplete, since it only takes
cognizance of E; and El, and ignores all other factors that might influence
‘M. The combined action of such factors is referred to as relaxation, which
was discussed previously. The complete Bloch equations taking relaxation

into account are

_Q = -i(wo~w)G+ inle - C/T2 (10a)

19

dM

Z
71-,- = -7H1My- (Mz-Mo)/T1 . (10b)

The Lineshape Equation with Exchange

The Bloch equation can be modified to include the effect of exchang-
ing nuclei (63,64). Consider a proton that can reside in two different
environments, A and B, with chemical shifts VA = (EDA/2n) and VB = (013/210 ,
and that jumps back and forth between A and B. A jump from.A to B results
in a decrease of magnetization in site A and a jump from B to A results

in an increase. A corresponding statement holds for the change of mag-
netization of B. McConnell (64) assumed that both the forward and reverse
reactions can be described by first-order rate laws with rate constants
kA-oB - l/rA and ICE-9A: l/TB, where TA and TB are the mean lifetimes at

sites A and B, respectively. The Bloch equations for the sites A and B

may therefore be modified to read

dG

A
dt "‘[1(“fif“» +»1/T2A]GA + inlM: - GA/rA + GB/rB (11a)

dG

B .
dt = -[i(u)B-<1)) + l/TQB]GB + ”HIM: - GB/TB + GA/TA . (11b)

Assuming that the system is in a state of equilibrium, the mean lifetimes
in sites A and B must have the same ratio as the corresponding fractional

populations p ,

TA/TB = pA/pB . (12)

20

In addition it is convenient to introduce a new variable

T=T

APB '1"

BpA . (13)

If one sweeps slowly through the resonance ("slow passage") the magneti-
zations will manage to follow "isothermally", that is, they become
stationary. It is also assumed that saturation is avoided by choosing a

low H1 field. These experimental conditions imply

M . (14)

Combining Equations (14) with (11) the modified Bloch equations become

linear equations in GA and GB:

1”A
-[i(wA-a>) + 1/“12A + pB/TlGA + 7GB =-ipA7H1Mo (15a)

PB . 1 .
? GA - [1((DB-(D) + /T2B + pA/T]GB = -1p

B7H1Mo - (15b)

These are easily solved if one defines
GA = ~[2ni(vA-v) + l/T2A + pB/T] (16a)
OB = -[2ni(vB-v) + l/TgB + pA/r] (16b)

0 = 7H1MO . <17)

21

where VA and VB are the chemical shifts in hertz relative to some standard

and C may be taken as an arbitrary scaling factor; the total transverse

magnetization, G = GAd-GB, is given by

'1CTIZPAPB - 1(pAOtB + pBClAH

G = . (18)
pApB " TgaAo‘s

 

The real part of Equation (18) gives the dispersion u mode lineshape
function and the imaginary part gives the absorption v mode lineshape
function over the entire sweep range v as a function of the parameters
VA, VB, T2A’ T23, pA, pB, and 1. These functions maybe written as (11)

'C{QP " [1+ 1(pB/T2A + pA/T‘QB) 1R]

u = P2 + R2 (19a)

 

-C{P[l+r(pB/T2A + pA/TQB)] + QR}

v = P2 +-R2 . (19b)

 

The quantities P, Q, and R are defined for convenience as

P = 'r[l/T2AT23 -(2n)2Av2 + (2fl)2(5v/2)2] + pB/T2B + pA/TgA (20a)
Q = 2mm - €35! (pA - 93)] (20b)
R = 2nAw[14-T(l/T2AeFl/T23)] + n18v(l/TgB-l/T2A) (20c)

where Aw = v-vo, Va is the average resonance frequency of VA and VB’ and

CV = vA- VB.

22

Activation Parameters

The activation energy for the exchange process in N,N-disubstituted
amides can be evaluated from the Arrhenius rate equation which is written

as (65,66)

k = A exp(-Ea/RT) , (21)
where k is the rate constant which is equal the inverse of twice the mean
lifetime (1), R is the molar gas constant, A is the frequency factor, and
E8 is the activation energy for internal rotation or the energy barrier
of the system. The quantities A and E

A

least-squares analysis from the experimental data for each amide.

can be evaluated by a linear

If one assumes that this exchange process obeys the absolute rate
equation (66), the entropy and enthalpy of activation, AS* and AH}, for
the internal rotation process can be written as

kBT * i
k = K -fi-exp(-AH /RT) exp(AS /R) , (22)

where r is the transmission coefficient, which is unity when every acti-
vated complex breaks up to give products, kB is the Boltzmann constant,
and h is Planck's constant. The free energy of activation at temperature

T°K can be found from the relationship

AS = AH - TAS . (23)

23

Chemical Shifts

Chemical shifts, for molecules without unpaired electrons, have their
origin in the magnetic screening of the nucleus which arises from the
orbital electronic currents induced by an external magnetic field (67).
These currents also give rise to diamagnetic polarization. When the
external magnetic field is Ho the total magnetic moment of the induced
current is XMHo where XM is the molecular diamagnetic susceptibility.

The secondary magnetic field due to the induced currents at any given
nucleus is -01Ho where 01 is the magnetic screening constant. The total
field experienced by a given nucleus, which determines its NMR frequency,

is given by (68)
N1 = Ho(l-oi) . (24)

The chemical shift may then be defined as

Hi - I'Iref
8 (ppm) = -—fi—'—-— X 106 , (25)

ref

where H1 is the resonant field of resonance being measured at a fixed
frequency and Href is the resonant field for a given reference. The chem,
ical shift may also be defined in terms of frequency as

vi - vref
6(ppm) = --;—-——— x 106 , (26>

ref

where v, is the resonant frequency of a signal being measured at a fixed

field and vref is the resonant frequency for a given reference.

24
From Equation (24) it is seen that the differences in the shieldings

of various nuclei are reflected by the differences in the screening con-
stants. The theory of screening constants first proposed by Saika and
Slichter (60) gives an atomic breakdown of diamagnetic currents. The
total screening constant for any atom A may be broken down into the fol-

lowing four terms:

0 =0

‘1 a
A AA + OIAA +21 UA13 + UA,r1ng . (27)

d
1304A)
The first term, 02A,

field at nucleus A due to diamagnetic currents on atom A itself. For an

is the contribution to the secondary magnetic

isolated spherical atom, it is the only contribution and is given explicitly

by the Lamb formula,

 

 

AA e2 -1
Cd = 3mc2 E: ri ’ (28)

where e is the charge of the electron, m is the electron mass, c is the

velocity of light, and r is the distance of the ith electron from the

i
nucleus, the sum being over all the electrons.

The second term, ogA, is the contribution due to the paramagnetic
currents on atom A, which gives the paramagnetic susceptibility. This term
was first calculated by Saika and Slichter who showed that for fluorine
atoms it was much more sensitive to chemical structure than 03A . For most
other nuclei, variations in this term will give the main contribution to

the chemical shift. The principal exception is hydrogen, where the absence

of low-lying atomic p-orbitals will make the paramagnetic term negligibly

small.

25

The third term, GAB, is the contribution to the screening of atom

B )

A by the atmmic circulations on atom B. When the magnetic effects of
these neighboring currents are treated in a dipole approximation, this
term involves only the local anisotropy of the local susceptibility on
atom B. If atom A is on, or near, the axis of high diamagnetism of B,
there will be an increase in the average screening. The effect falls off
as the inverse cube of the AB distance.

A,ring .

Finally, 0 is the contribution of the screening due to ring
currents which cannot be localized on any atom. The magnitude of this
term is usually small, except it does play an important part in deter-
mining the proton spectra of aromatic compounds.

For carbon-l3 chemical shifts the last two terms are relatively
unimportant, and calculations of the diamagnetic term, 0AA

d 9

is fairly constant for different types of carbon atoms. The paramagnetic

show that it

term, 02A , is therefore the dominant term in the expression for the
calculation of the shielding for the carbon-13 nucleus (70). Considerable
attention has been paid to the evaluation of this term using quantum

mechanical treatments (71,72).
Nuclear Spin-Spin Coupling

In 1951 Gutowsky, McCall, and Slichter observed that high resolution
Spectra frequently exhibited hyperfine structure which, in contrast to the
linear dependence of chemical shifts, was independent of the applied mag-

n-‘E!tic field (73,74). Similar effects had been observed by Hahn and Maxwell
it! the modulation of the spin-echo envelope in the pulse experiments (75).

1‘: was concluded that the observed effects were caused by an indirect

26

interaction of the nuclear moments pi, which is transmitted from nucleus
to nucleus by the paired electrons comprising the valence bonds. The
magnitude of this interaction is called the spin-spin coupling constant,.L

The interaction can be theoretically divided into three parts (76).
In the first of these, one nuclear magnetic moment induces orbital elec-
tronic currents which consequently induce magnetic fields at the site of
the second nucleus. In the second, the electron spin interacts with the
magnetic moment of one nucleus producing an electron spin polarization
which is then transferred to the adjoining nuclei. The third part, and
the most significant contribution to the overall spin-spin coupling, is
the Fermi contact interaction between nuclear spins and the spins of
electrons in s-orbitals, which produces an electron spin polarization pro-
portional to the density of the electrons at the nucleus.

In molecular orbital theory the spin-spin coupling constant, JAB’
may be written in terms of the wave functions of the ground and excited

states, W1 and W (77). Summing over occupied and unoccupied levels for

J
i and j, respectively,

OCC. UUOCC.

(I! ‘1’.) (‘II ‘1’)
- 1.1 A iAj B
JABa Z Z (G -<-: ) ’ (29)
1 j j 1

-e1) is the energy difference between the occupied ground state

 

where (c

J

6 and unoccupied excited states and is always positive. From the

6,,

above expression the sign of the coupling constant depends on whether the

i

unlecular orbital is symmetric or asymmetric. The symmetric molecular
orbitals have the same sign at atom A and atom B, and the asymetric molec-
ular orbitals have different signs. For transitions from symmetric to

symmetric or from asymmetric to asymmetric molecular orbitals, the

27

contribution to JAB is negative. Transitions from symmetric to asymmetric
molecular orbitals, or vice versa, gives a positive contribution to the

coupling constant.

Proton Decoupling

Spin decoupling, for the case where the coupled nuclei are of dif-
ferent species, involves the application of a second radiofrequency field
oscillating at the resonance frequency of the nucleus to be decoupled.
This causes the nucleus to change spin states so rapidly that its spin
vector no longer couples with the spin vectors of neighboring nuclei and
multiplets due to this coupling collapse.

In a simple AX molecule, the elimination of proton-induced splittings
can only be expected to collapse a doublet into a singlet, giving an en-
hancement of two-fold. Collapse of splittings in more complex molecules
such as benzene can result in a signal-enhancement figure approaching an
order of magnitude (78). The carbon-l3 magnetic resonance spectrum of
benzene (79) exhibits considerable proton splitting beyond the large doub-
let due to the directly bonded proton. These splittings are due to the
long-range couplings between a carbon-13 and the remaining hydrogens in
the molecule. The elimination of such complex splitting patterns leads to
a dramatic improvement in the signal-to-noise ratio. As most organic
molecules contain an even greater number of protons, benzene is by no
means an exception to the rule, and multiplet collapse can be considered
to give rise to about a lO-fold enhancement.

It should be Pointed out that such techniques eliminate much useful

information in the carbon-l3 spectrum, such as the coupling constants

28
between carbon and hydrogen. However, it may also be argued that the

chemical shift information obtained under proton decoupling conditions
is more readily acquired and interpreted. Elimination of proton split-
tings leads to spectral singlets which are free from all second-order
changes in line positions, and therefore shift data are obtained directly
from.the position of the spectral singlet. Also, the number of directly
bonded, geminal, and vicinal protons in most organic molecules will
produce splitting patterns of the carbon-13 resonance signal much more
complicated than is found in the corresponding proton resonance bonds.
Thus, it is concluded that the loss of spectral information may in many
instances be more than offset by the benefits of spectral simplicity,
which allows the chemical shift information to be obtained more readily

. and, in general, on a larger number of chemical systems.

In addition to the enhancement due to multiplet collapse, proton

decoupling techniques give rise to a nuclear Overhauser enhancement.
Nuclear Overhauser Enhancement

When the protons in a sample are decoupled by a strong irradiating
field, the effect on the carbon-l3 NMR spectrum is an enhancement of the
carbon-l3 signal due to a phenomenon known as the nuclear Overhauser effect
(NOE). The NOE results from dynamic polarization of the carbon-13 nuclei
when the proton resonances are saturated. This effect has been well
studied in carbon-l3 (80,81,82) and in nitrogen-15 (83) NMR.

The energy level diagram of a general two-spin system in a magnetic
field is given in Figure 3 where the energy levels in the absence of a

radiofrequency field have a Boltzmann distribution. When one nucleus is

29

 

 

 

Ba

Figure 3.

 

 

 

Energy-level diagram for an AX two-spin system in presence
of a magnetic field.

30

irradiated by a radiofrequency field the other nucleus is enhanced by the

nuclear Overhauser enhancement, 6, of

9 = l + nA-{x} , . (30)

where

= (yx/yA)<w2x-W§x)/<WS5‘+2WI+R§X) . <31)

nA-{x}

Equation (31) can be rewritten for proton and carbon-l3 nuclei as

7
= .3. 2 2 *
TIc-{H} . 27C [K EJni/(K §Jm+4wlc) ’ (32)

where 7H and 7C are the magnetogyric ratios of 1H and 13C nuclei, respec-
tively, K = hynyc/Zx, JDi is the spectral density at the carbon-13 fre-
quency arising from.the fluctuating dipolar interaction between proton i
and the carbon-13 nucleus, and W1: represents all other relaxation contri-
butions proportional to the carbon-13 z-magnetization, (12), other than
dipolar.

If the dipole mechanism is dominant, i.e. , 4W1:((K22EJ Equation (32)

Di’

reduces to

nC-{H} = (7H/270) = 1.988 (33)

and the Overhauser enhancement is 9 = 2.988. This is the maximum theoret-
ical enhancement and other relaxation mechanisms will reduce this value.
Kuhlmann and Grant (82) have measured the enhancement in formic acid and

have found it to be 2.98.

31
When the dipole mechanism dominates, the number of nearest neighbor

protons does not effect the enhancement since K?§.I drops out of Equation

Di
(32). If other relaxation mechanisme are present the number of nearest

neighbor protons can lead to variations in the value of nC-{H}'

Kuhlmann, Grant, and Harris (80) have shown that

d(I )

dtz = (%’K2Z1;JD1+2W1:)(<IZ) - 9<IZ)O) , . (34)

 

where (Iz)o is the equilibrium magnetization in the absence of proton
decoupling. The relaxation of enhanced carbon-l3 nuclei is still governed

by a single time constant, T1, given by

l. ...1. 2 *
T1 -2K §J01+2W10 . (35)

Equation (35) combined with (32) yields

K2? JDi = 4(70/711) (nC-{H}/Tl) (36)
and

WE; = [1-(27C/7H)nC-(H]]/2T1 . (37)

Therefore, W12," and K2); JDi can be calculated from the measured values of
1

the Overhauser enhancement and the spin-lattice relaxation time.

32

Lanthanide Induced Chendcal Shifts

Since the discovery by Hinckley (84) that large isotropic shifts are
produced in the proton resonances of cholesterol when this molecule is
placed in solutions of the dipyridinate of tris(dipivaloylmethanato)
eurOpium(III), Eu(dpm)3(py)2, considerable interest has been shown (85-
101) in lanthanide "shift reagents". Some of the major discoveries are:
(a) the finding that shift reagents cause isotropic shifts in a variety
of functional organic molecules including alcohols (84,85-90,94,95),
amines (85,91,96), ketones (85,92,94), aldehydes (85,96), and esters
(93,94,96,97); (b) the observation (85) that Eu(dpm)3 is more efficient
in effecting such shifts than is Eu(dpm)3(py)2; (c) the discovery (86)
that Pr(dpm)3 causes upfield shifts of larger magnitude than the down-
field displacements induced by Eu(dpm)3; also, the observation (94) of
shifts for substrates in the presence of dpm.complexes of Sm,Tb,Ho and
Yb; (d) the observation that certain other lanthanide complexes (86), as
well as B-diketonate chelates with less bulky substitutes than Ln(dpm)3,
are inadequate as shift reagents (96); (e) the finding (97) that partially
fluorinated chelates of a similar variety are superior shift reagents
because of greater solubility and greater Lewis acidities; and (f) the
observation that shift reagents can be applied to study NMR spectra of
nuclei other than protons (99-101).

The action of shift reagents is generally attributed to a through-
space dipolar interaction (102,103). Dipolar shifts are proportional to
the magnetic susceptibility anisotropy (102), and to the geometric factor

((3 c0329-1)r'3) , where r is the length of a radius vector from.the metal
AV

33

atom to the resonating nucleus, 6 is the angle made by this vector with
the principal axis, and the average is taken over motions rapid on the

NMR time scale.

EXPERIMENTAL

Preparation of Compounds

Methanol Enriched in Carbon-l3 --- In order to locate carbon-l3

 

resonances on our spectrometer it was necessary that a sample enriched
in carbon-l3 be prepared. The preparation of carbon-13 enriched methanol
was performed by first converting enriched barium carbonate to carbon
dioxide and then reducing the carbon dioxide to methanol (104,105).

Concentrated hydrochloric acid was added slowly to 0.05 moles of
57.2 percent carbon-l3 enriched barium carbonate (Isomet Corp., Palisades
Park, N.J.). The carbon dioxide generated was passed directly into a
0.5 M solution of lithium aluminum hydride in diethyl carbitol under a
nitrogen atmosphere. The methanol was liberated by alcoholysis with the
addition of one mole of g-butyl carbitol. Diethyl carbitol was selected
as the solvent and n-butyl carbitol as the liberating agent because of
their high boiling points which left methanol as the most volatile com-
ponent of the system. The methanol was then obtained by simple distil-
lation. The Yield of methanol was approximately 75 percent, based on the
amount of carbon dioxide generated.

N,N-Dimethyldichloroacetamide and N,N-Dimethyltrichloroacetamide ---
The preparation of N,N-dimethyldichloroacetamide and N,N-dimethyltri-
chloroacetamide was performed by following a general procedure for
tertiary amides (106,107). An aqueous solution of one mole of sodium

hydroxide was added slowly and with stirring to one mole of aqueous
34

35
dimethylamine. One mole of the appropriate acetyl chloride, in this case

dichloroacetyl chloride or trichloroacetyl chloride, was then added to
the basic amine solution, while maintaining the temperature between five
and ten degrees Centigrade. After completion of the reaction, the mix-
ture was neutralized and the aqueous solution was extracted with diethyl
ether four times. The ether extracts were combined and dried overnight
over anhydrous potassium carbonate. The ether was removed by distilla-

tion, and the product was purified by fractional distillation ig_vacuo.
Physical Constants of Compounds Studied

All of the amides studied in this research are listed in Table 5
(N-monosubstituted amides), Tables 6 and 7 (symmetrically N,N-disubsti-
tuted amides), and Table 8 (unsymmetrically N,N-disubstituted amides).
Boiling points or melting points are also given in these tables. The
purity of each amide was determined by examination of its proton NMR
spectrum. An amide was considered to be impure if there were unexplain-
able peaks in the proton NMR spectrum. If the amide was impure, it was
purified by drying over anhydrous sodium sulfate and fractionally dis—
tilling ig,y§ggg. .

The chemical shift reagents tris(l,l,l,2,2,3,3-heptafluoro-7,7-
dimethyl-4,6-octanedionato) europium(III), Eu(fod)3, and tris(l,l,l,2,2,-
3,3-heptaf1uoro-7,7-dimethyl-4,6-octanedionato) praseodymium(III), Pr(fod)3,
were purchased from the Norell Chemical Company, Landing, New Jersey. The
shifts reagents were stored over phosphorous pentoxide in a vacuum desicca-

tor.

36
Table 5. N-Monosubstituted amides studied.

 

 

Compound Source
N-Methylformamide A
NAMethylacetamide A
N-Methylpropionamide A
N4Methy1isobutyamide B
N-Methylpivalamide B
N-Ethylformamide A
N-Ethylacetamide A
N-Ethylpropionamide B
N-Ethylisobutyramide B
N-Isopropylformamide B
N-IsOpropylacetamide B
N-Isopropylisobutyramide B
N-ngutylformamide B
N-ngutylacetamide B
NfigyButylformamide B

Boiling
Pointb

56/6
80.0-81.0/2
89.0-90.3/2
78.0-78.5/2.5
M.P. 90.4-91.0
63.2-64.0/1
80-83/1.5
78.5-79.5/2.5
M.P. 69.0-71.0
7o/1.5
86.5-87.0/4
M.P. 102

81/1

111/6

67/1.5

 

aA - Eastman Organic Chemicals, Rochester, New York.
B - Prepared by L. A. LaPlanche in this laboratory (107).

bGiven as: °C/mm.

Table 6. N,N-Dimethylamides studied.

37

 

 

 

Boiling
Compound Sggggg Point

N,N-Dimethylformamide A 31.5-34.0/25
N,N-Dimethylformamide-dlc B
N,N-Dimethylacetamide C 44.0-45.0/3
N,N-Dimethylpropionamide C 51.0-52.0/3
N,N-Dimethyl-gfbutyramide C 47.0-47.5/O.5
N,N-Dimethylisobutyramide D 55/3
N,N-Dimethylp iva lamide 0 73/2. 5
N,N-Dimethylchloroacetamide E 72.5-73.0/2
N,N-Dimethyldichloroacetamide F 96.5/11
N,N-Dimethyltrichloroacetamide F 77/2
N,N-Dime thylcarbamylchloride E 78/39
N,N-Dimethyltrifluoroacetamide G 134,3/740
N, N-Dime thy lacrylamide E 46/3
Ethyl-N,N-dimethylcarbamate G 142/733

 

- Matheson, Coleman and Bell, East Rutherford, New Jersey.
- Merck, Sharp and Dohme of Canada Limited, Quebec, Canada.
- Eastman Organic Chemicals, Rochester, New York.

Received from L. A. Graham, Northern Illinois University.
- Pfaltz and Bauer, Flushing, New York.

- Prepared in this laboratory.

- Prepared by J. C. Woodbrey in this laboratory (108).

0mm000>
I

bGiven as: °C/mm.

cStudied without further purification.

38

Table 7. Other symmetrically N,N-disubstituted amides studied.

 

Compound
N,N-Diethylformamide
N,N-Diethylacetamide
N,N-Diethylpropionamide
N,N-Diethyl-nybutyramide
N,N-Diethylchloroacetamide
N,N-Diethylacrylamidec
N,N-Diisopropylformamide
N,N-Diisopropylacetamide
N,N-Diisopropylpropionamide
N,N-Di-gfpropylformamide

N,N-Di-nypropylacetamide

a
Source

45.
60.
53.

61.

72

69.

56.

62.

60.

68.

Boiling
Point

0/48.0/2
5-61.5/2
0-54.o/1.5

0-63.0/1

.0-73.0/2

o-71.0/7
0/1
0-62.5/0.5
5-61.5/2.5

0-68.3/5

 

0060:»
I

bGiven as: °C/mm.

cStudied without further purification.

Matheson, Coleman and Bell, East Rutherford, New York.
Eastman Organic Chemicals, Rochester, New York.

K&K Laboratories, Inc. , Jamaica, New York.

Prepared by L. A. LaPlanche in this laboratory (107).

39

Table 8. Unsymmetrically N,N-disubstituted amides studied.

 

Compound
N-Ethyl-N-methylformamide
N-Ethyl-N—methylacetamide
N-Ethyl-N-methylpivalamide
N-Isopropyl-N-methylformamide
N-Isopropyl-N-methylacetamide
anfButyl-N-methylformamide
Nfingutyl-N-methylacetamide
Nfngutyl-N-methylisobutyramide
anfButyl-N-methylpivalamide
Nfithutyl-N-methylformamide
NngButyl-N-methylacetamide
N—Cyclohexyl-N-methylacetamide

l-Methyl-Z-pyrrolidinone

Source

>*

>'

>- >' I>

a

Boiling
Pointb

 

82.0/44
45.0/33
62.0-63.0/5
58.5/7
60.0/17
55.0-56.0/1
65.0/3
72.5-73.0/2.5
75.0-76.0/2
64.5/5
56.5/5
130/13

202/760

 

aA - Prepared by L. A. LaPlanche in this laboratory (107).

B - Eastman Organic Chemicals, Rochester, New York,

C - Aldrich Chemicals, Milwaukee, Wisconsin.

bGiven as: °C/mm.

4O

Spectrometer

In this investigation, spectra were obtained on a Varian HA-lOO high-
resolution nuclear magnetic resonance spectrometer. The main magnetic
field of 23,490 gauss was generated by a V-4014 twelve-inch high-impedance
electromagnet equipped with a V-2100B regulated magnet power supply.
Stability of this magnetic field was maintained to better than one part
in 108 by a V-3506 flux stabilizer.

The system is capable of observing either proton resonances at 100
MHz or carbon-l3 resonances at 25.1 MHz. In each case, the crystal-
controlled radiofrequency is produced by a separate V-4311 fixed frequency
rf unit. The radiofrequency is transmitted to a V-4333 variable tempera-
ture probe where the resonance of the sample is detected by the crossed-
coil method. The carbon-l3 probe was double tuned so that the carbon
resonances could be examined while irradiating the proton resonances to
remove the coupling between the two nuclei. The pseudo-random noise at
100 MHz was generated by a V-3512 noise decoupler. A V-4354A internal
reference NMR stabilization unit modulated the radiofrequency with two
audio frequencies; one frequency, called the analytical channel, was used
to detect the resonances in the sample and the other frequency, called
the control channel, was used to lock the magnetic field to a reference
frequency. The reference was one of the sample resonance frequencies or
that of an added internal standard. Frequencies were counted with a
Hewlett-Packard 5245L frequency counter.

In order to observe a carbon-l3 spectrum it was necessary to work at
the highest gain of the spectrometer. Working at this ultimate limit of

the spectrometer produced an undesireable rolling baseline, as shown in

41

Figure 4, as the result of a large modulation index. The modulation
index (110) is a dimensionless quantity, the ratio between the frequency
deviation, in hertz, and the modulation frequency, also in hertz. When
the audio frequency is swept, the modulation index is large and the am-
plitude of the modulation signal varies greatly. The phase-sensitive
detector used to detect the NMR signal is sensitive to changes in the
modulation signal, which is normally small under the usual operating con-
ditions of the spectrometer. However, under the conditions employed for
the carbon-l3 NMR experiment these changes are very large and are re-
flected in the spectrum.

In order to conduct the variable temperature studies it was neces-
sary to stabilize the temperature of the probe and measure this tempera-
ture accurately. Temperature stability was maintained in the range of
~60 to 200°C by a V-4343 variable temperature accessory connected to a
heater sensor in the probe. Temperature calibration for the proton work
was accomplished by using the chemical thermometers methanol and ethylene
glycol. In the high temperature range, 30°C to 200°C, the temperature

was found from the expression (109)

T°K = -(8EG) 1.017 + 464.9 , (38)

where SE is the chemical shift difference between the two chemical shifts

G
of the protons in ethylene glycol at 100 MHz. In the low temperature

range, -100° to 30°C, the calibration equation is (109)

T°K = -(8M) 1.076 + 464.7 , (39)

42

.ooaamcowoouaahnuofiolz.z mo aouuooam mzz manoooumo .0 madman
Eco . may“
0. n. on am On an on no . c N:
_ _ _ _ In a _ _ . _

 

 

 

 

 

 

 

43
where 5M is the difference between the two chemical shifts of the protons

in methanol at 100 MHz. The temperature calibration for the carbon-l3
spectra was accomplished by using a copper-constantan thermocouple be-

cause no carbon-13 chemical thermometer has been found.
Time Averaging and Digitization of Spectra

The Varian HA-lOO was interfaced with a Varian C-1024 computer of
averaged transients (CAT). When a spectrum of interest is swept repeat-
edly, signal information is added into memory channels of the C-1024 in
direct proportion to the number of sweeps, while random noise is accumu-
lated in proportion to the square root of the number of sweeps. The sen-
sitivity of the NMR experiment, especially for carbon-13 spectra, is
increased by accumulating repeated sweeps of the spectrum. Frequency
calibration is accomplished by reading the information stored in memory
out on to a recorder precalibrated to the spectral sweep width.

The C-1024 was also used to digitize a spectrum of interest for which
purpose it was connected to a Varian C-1001 binary-to-octal coupler
attached to a IBM 526 key punch. The punched cards containing the 1024
points in an octal format were read into a CDC 6500 computer for further
processing. The C-1024 operated exclusively in this mode for the total

lineshape analysis portion of this investigation.
Sample Preparation

All proton and carbon-13 spectra were obtained by placing the samples

in five millimeter, precision-ground, NMR tubes.

44

The tertiary amides for the hindered internal rotation studies were
degassed and sealed by the freeze-pump-thaw method to remove any trace
amounts of paramagnetic oxygen which broadens the NMR lines. The addi-
tion of five percent by volume of either tetramethylsilane (TMS) or hexa-
methyldisiloxane (HMDS) was required in each sample to provide a refer-
ence and lock signal. The substituted formamides, which have very high
coalescence temperatures, were degassed and sealed in three millimeter
tubes and placed in five millimeter NMR tubes containing tert-butyl
benzene (TBB). The methyl resonance of TBB provided the reference and
lock signal.

Solutions of the tertiary amides used in the resonance assignment
study were initially 0.2 M in carbon tetrachloride and the shift reagent
[Eu(fod)3 or Pr(fod)3] was then added in increments up to a mole ratio
of 0.4 (shift reagent to amide). Five percent by volume of TMS was added
to each sample as an internal reference. The proton NMR spectrum was
examined prior to and after each addition of the shift reagent. The
series of spectra for each amide were acquired at a temperature well be-
low the coalescence temperature._

The carbon-13 NMR spectra were obtained by placing the sample in a
five millimeter NMR tube with a capillary containing 57% carbon-l3 en-
riched methanol. The capillary was centered by means of a Teflon plug.
The enriched methanol was used as a reference and lock signal. When
necessary the spectra were run at temperatures low enough to slow the

internal rotation and permit observation of both isomers.

45
Bulk Diamagnetic Susceptibility Corrections

Where an external reference is used, a correction involving the
difference between the bulk diamagnetic susceptibilities of the reference
compound and the sample must be applied. This is necessitated by the
fact that, in cylindrically shaped containers, the actual fields experi-
enced by individual nuclei will depend on the magnetic polarization near

the surface. ,The correction for a cylindrical sample is

2n

SCORR ..— E’0133 + '3— (Xv,ref ' Xx) ’

(40)
where 8 is the chemical shift in ppm and Xv is the volume diamagnetic
susceptibility (68).

The volume diamagnetic susceptibilities of several compounds were
measured by the Gouy method (111). The measurements were made on a mag-
netic susceptibility system manufactured by the Alpha Scientific Company.
The measured values are given in Table 9. The chemical shift corrections

Table 9. Volume magnetic susceptibilities and bulk
magnetic susceptibility corrections for several compounds

 

2x

 

 

Compound - X T (Xv,CH30H - Xv)
Methanol 0,525 ppm ._
N-Methylformamide 0.564 ppm 0.081 ppm
N-Methylpropionamide 0.619 ppm 0.197 ppm
N,N-Dimethylformamide 0, 58 1 ppm 0. 117 ppm
N,N-Diethylformamide 0,579 ppm 0,113 ppm
N,N-Diethylacetamide 0.615 ppm 0.188 ppm

 

46

\

for several amides (with methanol aA\the reference) are also given in
this table. The correction factor for formamides is approximately 0.1
ppm and for other amides it is about 0.2 ppm. Since these corrections
are within the experimental error of measurement of the chemical shifts
in the carbon-l3 spectrum, no bulk diamagnetic susceptibility corrections

‘were made for the carbon-13 chemical shifts.
Determination of Energy Barriers for Hindered Internal Rotations

The rate of internal rotation about the C-N bond in several amides

 

was obtained by an iterative computer fitting of the theoretical spec-
trum, calculated from the total lineshape equations as derived by Rogers
and Woodbrey (11), to the experimental spectrum.

The curve fitting program was developed by Dye and Nicely (112).

The program minimizes the functional

n
q) =ZW1F12 , (41)
i=1

in which n is the number of data points, F1 is the residual defined in
such a way that it would approach zero for all i as the parameters
approach their "best" values if the data were completely free from errors,
and W1 is a weight which was set to unity for all points; if desired Wi
can be calculated by the program. The general program will fit an arbi-
trary function of not more than 20 parameters (dependent plus independent)
to a data set containing a maximum of 99 points.

The lineshape equation is a function of the spin-spin relaxation

times at sites A and B (T2A’ T23), the chemical shift difference (8v) in

47

the absence of exchange, the relative population at each site (pA, pB),
and the mean lifetime (1) at each site. These parameters were determined
above and below the coalescence temperature for the Ndmethyl protons in
each amide by the following techniques. The proton NMR spectrum of each
amide was examined at a temperature well below the coalescence temperature
to establish an estimated value of each parameter (except 1). In the
temperature region below coalescence all of the parameters were deter-
mined by simmltaneous iteration to obtain the best fit to the experimen-
tal lineshape. The final value of each parameter calculated was examined
for experimental feasibility. For temperatures above coalescence, the
experimental lineshape contains insufficient information to allow the
simultaneous determination of all the parameters. In this case, all of
the parameters except the mean lifetime (1) at each site were held con-
stant at a value which was the average of those calculated from the experi-

mental curves below the coalescence temperature.

RESULTS

Hindered Internal Rotation in Tertiary Amides

rev.
The barrier to internal rotation about the central C-N bond for a i
series of tertiary amides, symmetrically and unsymmetrically substituted, %
7
was studied by total lineshape analysis. The proton NMR spectrum of the I
N-methyl protons was obtained at several temperatures above and below ’3

the coalescence temperature. The experimental curve at each temperature
was then fitted to the theoretical lineshape equation in order to extract
the parameters of interest. The proton NMR spectrum for each amide can

be found elsewhere (107,108,109).
Symmetrically Disubstituted Amides

N,N-Dimethylacetamide --- The barrier to internal rotation for neat
N,N-dimethylacetamide was studied at various temperatures by fitting the
experimental curve of the N-methyl resonances to the theoretical line-
shape equation. The parameters in the theoretical equation were then
adjusted by an iteration procedure to obtain the fit. Four of these plots
are shown in Figures 5-8. In these figures, X's designate experimental
points, 0's designate calculated points, and ='s designate an experimental
point and a calculated point which are in the same area element delta x by
delta y. The experimental data obtained are given in Table 10. The loga-

rithm of the rate constant is plotted against 103/T°K in Figure 9.
48

49

.Mem.m~m R 9 up oofismuoomamnuoafivuz.z use:

 

aw mdououo Hhsumsuz new no mamawfim A00 moumaooamo mam Axv oo>uomno .m whomwm
o 0800 0
x xxx 0 ouuu..x
XXX 0 nun X
.8 8800000000 3
x0 «an xxxxxx xxxxx 0 o n
x O: x x0 «x
o u x x0 4
x 4 x0 0
n X X
o a o
X I X u
0 n
X n
o _
x
x
A o
x
o x
o
u x
o
x
x o
o
x
x
0 o
x
o
x
0 x x
x o
o 0
u o
u Ox
x

 

 

 

50

 

.MoH.o¢m I H. um ngumumfihfiumafifi Z.
I 2 anon
5 3398 130812 on”. no 36:36 80 33333 one 03 350.30

.0 ousmwm

 

OX

0 X
n
u

OX
00
X0

X0

 

 

 

51

 

 

erode n e um SESSSESEEAE use:
:a moououm Hanuoalz man no mamcwfim A00 omumaooamo 0am Axv om>uomno

.n ouowfim

 

 

OX
X0
.0

OX
X

 

 

52

rib

 

.Mom.wcm
6H maououo HanuoEIz onu mo

 

N H on unassumooahguoaaeuz.z umoa
mamawwm A00 ooumasoamu can Axv oo>uomno .w ouswfim

 

 

M

00 u

uuquuuuquuuuuunuu

O

 

 

53

Table 10. Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N,N-dimethylacetamide.i

 

r°1< 103/ Tog 1 1n( 1/2.) 517*

 

 

 

 

.299... _______._ .112. FA
325.7 3.071 .1181 1.443 17.7 .498
331.8 3.014 .0608 2.106 17.8 .503
335.1 2.984 .0419 2.480 17.6 .505
335.1 2.984 .0393 2.544 17.8 .496
337.3 2.965 .0331 2.716 17.2 .489
340.1 2.940 .0244 3.021 17.7 .503
343.0 2.916 .0213 3.157 17.5 .501
346.2 2.888 .0162 3.431 17.8 .500
348.5 2.870 .0138 3.586
350.8 2.851 0.0113 3.788
354.4 2.822 0.0084 4.082
358.1 2.792 0.0067 4.317
362.3 2.760 0.0051 4.594
E8 = 19.7 i 0.5 kcal/mole logloA = 13.9 i 0.4
AG*zgg= 18.1-i 0.5 kcal/mole 0H5 = 19.0 i 0.5 kcal/mole

43* = 2.9 i 1.4 eu

Coalescence temperature = 348°K

-*
Results from total lineshape analysis.

 

lav/2r)

4&6C"

4&20

3m30

3040

3K“)

126C)

ELZO

|.80

1440

54

 

.. O

 

 

1 n I J l 1 1 J
279 2.93 2.87 2.9: 2.95 299 3.03 3.07
Io3/T°K

Figure 9. Plot of ln(l/27) against 103/T°K for neat
N,N—dimethylacetamide.

7']

—-.—‘—v- “‘4'; ‘1 v—- v—- —

L

55
NLN-Dimethylcarbamylchloride --- Hindered internal rotation in neat

N,N-dimethylcarbamylchloride was studied by total lineshape analysis.

The experimental data and calculated activation parameters are given in
Table 11. The logarithm of the rate constant is plotted against 103/T°K
in Figure 10.

. ELN-Dimethylformamide --- The proton resonances of the N-methyl pro-
tons in N,N-dimethylformamide are split into doublets due to coupling with
the formyl proton. The trans coupling constant is 0.8 Hz and the gig
coupling constant is 0.5 Hz. The barrier to internal rotation for this
amide was studied by two methods.

Method I. The coupling to the formyl proton was neglected and the
experimental curves were analyzed as a two-site case. The experimental
activation parameters calculated by this method are given in Table 12.

The logarithm of the rate constant is plotted against 103/T°K in Figure
11.

Method 11. The coupling to the formyl proton was taken into consid-
eration by assuming the pair of doublets to be a consequence of the super-
position of two doublets (109) whose centers are separated by (Jci +

S

Jtrans)/2' The experimental spectrum was then fitted to the theoretical
lineshape equation which had been modified to include the coupling con-
stants. The experimental data and the activation parameters calculated
are given in Table 13. The logarithm of the rate constant is plotted
against 103/T°K in Figure 12.

NLN-Dimethylformamide-dl --- The effect of coupling by the formyl
proton was removed by replacing this proton with a deuteron. The hindered

internal rotation was studied by total lineshape analysis and the experi-

mental data and the calculated activation parameters are tabulated in

 

56

Table 11. Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N,N-dimethylcarbamylchloride.

 

 

 

 

 

T°K 103/T°K 1* 1n(1/21) 8v* pA*
sec _§§_

303.8 3.292 0.1623 1.125 10.8 0.498
308.7 3.239 0.0921 1.692 10.7 0.494
311.4 3.211 0.0746 1.903 10.8 0.502
316.0 3.165 0.0472 2.360 11.0 0.503
316.4 3.161 0.0481 2.341 10.7 0.492
319.3 3.132 0.0312 2.733 11.1 0.497
321.3 3.112 0.0240 3.036 11.5 0.506
323.5 3.091 0.0214 3.150
325.6 3.071 0.0198 3.230
328.8 3.041 0.0141 3.568
330.7 3.024 0.0130 3.647
E8 = 16.7 i 0.6 kcal/mole logloA = 13.9 i 0.4
063293 = 17.1 i 0.6 kcal/mole AH3 = 18.0 i 0.6 Real/mole

* +

AS = 3.0 - 1.8 an

Coalescence temperature = 324°K

*
Results from total lineshape analysis.

luv/21')

57

4.20 "

3.40
3.00
2 .60
2.20
I .80

L40

 

1.00 -

 

11111111

3.02 3.06 am 3.:4 3.Ia 3.22 3.26
103/T’K

 

Figure 10. Plot of 1n(l/21) against 103/T°K for neat
N,N-dimethylcarbamylchloride.

 

58

Table 12. Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N,N-dimethylformamide - Method I.

 

 

 

 

 

 

1--'--- -- -"‘—~ '- -~'y
4‘.

K3

l

T°K 103/T°K 7* 1n(1/21) 0v* pA*
sec Hz

383.2 2.609 .0499 2.304 15.0 0.500
386.3 2.589 .0381 2.575 14.9 0.498
387.3 2.582 .0357 2.639 15.1 0.505
389.3 2.568 .0312 2.773 14.9 0.503
391.7 2.553 .0276 2.897 15.3 0.509
392.7 2.546 .0257 2.968 15.2 0.504
394.4 2.535 .0240 3.036 15.1 0.496
394.8 2.533 .0228 3.089 15.2 0.506
395.4 2.529 .0218 3.134 15.4 0.510
395.7 2.527 .0202 3.207 14.9 0.501
397.2 2.519 .0196 3.241
398.2 2.511 .0174 3.359
399.4 2.504' .0171 3.378
E8 = 19.8 i 0.5 kcal/mole 10g1oA = 12.3 i 0.4
AG:t = 20.4 i 0.5 kcal/mole Afli = 19.0 i 0.5 kcal/mole

43* = -4.7 t 1.5 eu

Coalescence temperature = 397°K

*
Results from total lineshape analysis.

 

59

 

 

 

. c u
3.70 _ H’ \cu,
350 -
3.30 r-

: 3.:0 —
s“

5.

2.90 -
2.70 -
2.50 -
2.30 —
l 1 I 1 l 1
2.50 2.52 2.54 2.55 2.58 2.60
' I03/7°K

Figure 11. Plot of 1n(1/21) against 103/T°K for neat
N,N-dimethylformamide - Method I.

Table 13.

Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N,N-dimethylformamide - Method II.

60

 

 

 

 

 

 

T°K 10?/T°K 1* 1n(1/21) 5v* pA*
229.. Hz

386.3 2.589 .0469 2.367 14.9 0.502
387.3 2.582 .0433 2.450 14.9 0.505
389.3 2.568 .0368 2.610 14.8 0.498
391.7 2.553 .0285 2.866 15.2 0.509
392.7 2.546 .0275 2.901 15.1 0.497
394.4 2.535 .0240 3.037 15.2 0.507
394.8 2.533 .0242 3.030 15.4 0.510
395.4 2.529 .0222 3.115 14.8 0.498
395.7 2.527 .0219 3.127

397.2 2.518 .0197 3.232

398.2 2.511 .0174 3.360

399.4 2.504 .0170 3.380
Ea - 24.3 .5 kcal/mole logloA = 14.8 i 0.4

£03293 3 21.5

1

AB = 6.5 i 2.

i 0.5 kcal/mole

0 eu

Coalescence temperature = 397°K

¢

AH =

*
Results from total lineshape analysis.

23.5 i 0.5 kcal/mole

in (V2?)

3.70

3. 50

3.30

3.I0

2.90

2.70

2.50

2.30

61,

 

 

 

P
1 1 1 1 1 1
2. 50 2.52 2.54 2. 56 2.58 2.60
Io3/T°K

Figure 12. Plot of ln(1/2T) against 103/T°K for neat
N,N-dimethylformamide - Method II.

62
Table 14. The logarithm of the rate constant is plotted against 109/T°K

in Figure 13.

ELM-Dimethylpropionamide --- Hindered internal rotation in N,N-
dimethylpropionamide was studied in the neat liquid by total lineshape
analysis and the experimental data and the calculated activation paramp
eters are tabulated in Table 15. The logarithm of the rate constant is
plotted against 103/T°K in Figure 14.

M,N-Dimethyltrichloroacetamide --- Hindered internal rotation in
N,N-dimethyltrichloroacetamide in the neat liquid was studied by total
lineshape analysis and the experimental data and the calculated activa-
tion parameters are tabulated in Table 16. The logarithm of the rate

constant is plotted 103/T°K in Figure 15.
Unsymmetrically Disubstituted Amides

N-Ethyl-N-methylacetamide --- Hindered internal rotation in N-ethyl-
N-methylacetamide in the neat liquid was studied by total lineshape analy-
sis of the N-methyl proton resonances. The experimental data and the
calculated activation parameters are tabulated in the Table 17. The log-
arithm of the rate constant is plotted against 103/T°K in Figure 16.

N-EfButyl-N-methylacetamide --- Hindered internal rotation in N-nf

 

butyl-N-methylacetamide in the neat liquid was studied by total lineshape
analysis of the N-methyl proton resonances. The experimental data and
the calculated activation parameters are tabulated in Table 18. The
logarithm of the rate constant is plotted against 109/T°K in Figure 17.
N-Cyclohexyl-N9methy1acetamide --- Hindered internal rotation in N—

cyclohexyl-N-methylacetamide in the neat liquid was studied by total

63

Table 14. Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N,N-dimethylformamide-dl.

 

 

 

 

 

T°K 103/1°K 1* 1n(1/21) 59* pA*
_§2£._ __.___... Hz

370.3 2.700 0.279 0.583 15.0 0.506
373.9 2.675 0.217 0.835 15.2 0.502
379.0 2.639 0.118 1.446 15.0 0.499
383.5 2.607 0.0805 1.827 15.0 0.503
388.6 2.573 0.0651 2.038 14.9 0.496
397.8 2.514 0.0243 3.025 15.0 0.497
403.9 2.476 0.0169 3.390 15.1 0 501
407.5 2.454 0.0119 3.737
412.5 2.424 0.0082 4.105
417.1 2.397' 0.0056 4.491
422.2 2.369 0.0043 3.749
Ea = 25.3 i 0.3 Real/mole logloA = 15.2 1 0.2
AG*298 = 22.1 i 0.3 kcal/mole AH3 = 24.6 i 0.3 kcal/mole
28* = 8.5 i 1.2 an

Coalescence temperature = 404°K

*
Results from total lineshape analysis.

fin (V2?)

5.0

4.0

3.0

2.0

[.0

0.0

64

 

 

 

 

_-
L.
l l l I l
2.3 2.4 2.5 2.6 2.7
103/7°K

Figure 13. Plot of ln(1/21) against 103/T°K for neat
N,N-dimethylformamide-d1.

65

Table 15. Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N,N-dimethylpropionamide.

 

 

 

 

 

 

T°K 103/T°K 1* 1n(1/21) 5v* pA*
sec Hz

314.2 3.183 0.0785 1.851 14.4 0.508
319.2 3.133 0.0455 2.396 14.5 0.504
321.0 3.115 0.0390 2.551 14.8 0.492
321.0 3.115 0.0393 2.545 14.5 0.504
322.2 3.103 0.0395 2.538 14.7 0.502
322.2 3.103 0.0358 2.640 14.8 0.507
323.5 3.091 0.0294 2.833 14.5 0.498
-323.6 3.090 0.0289 2.851 15.0 0.495
325.9 3.069 0.0268 2.928 14.7 0.502
325.9 3.069 0.0268 2.925 14.9 0.496
326.2 3.066 0.0249 2.300

327.5 3.053 0.0228 3.088

327.9 3.050 0.0209 3.176

329.3 3.036 0.0194 3.250

330.5 3.026 0.0172 3.369

332.9 3.004 0.0139 3.582

334.8 2.987 0.0118 3.750

337.2 2.966 0.0096 3.950

E8 = 18.9 i 0.4 kcal/mole logloA = 13.9 i 0.3

40*296 = 17.2 i 0.4 kcal/mole AH" = 18.2 1 0.4 kcal/mole

83* = 3.1 t 1.2 eu

Coalescence temperature = 331°K

*
Results from total lineshape analysis.

66

4.20 - . 1'

3.80

 

3.40

an (yfi‘r',

3.00

2.60

2.20

1.80

 

 

I l l l l l
2.98 3.02 3.06 3.10 3.14 3.18

103/T°K

 

Figure 14. Plot of 1n(1/21) against 103/T°K for neat
N,N-dimethylpropionamide.

Table 16. Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat N,N-dimethyltrichloroacetamide.

67

 

T°K

 

283.2
286.6
288.0
290.1
292.1
295.0
296.8
298.2
303.6

306.9

103/T°I(

3.531
3.489
3.472
3.447
3.423
3.390
3.369
3.353
3.294

3.259

*
T

sec

 

0.0326
0.0233
0.0202
0.0171
0.0124
0.0106
0.0081
0.0074
0.0047

0.0033

1n(l/21)

1.729
3.067
3.207
3.378
3.695
3.851
4.119
4.212
4.666

5.030

*
5v
Hz

 

29.3
29.2
29.1
29.2
29.0
29.2

29.1

 

0.498
0.496
0.504
0.512
0.502
0.495

0.501

 

Ea = 16.7 i 0.3 kcal/mole

£67293 = 15.0 i 0.3 keel/mole

AB* =

1.1 eu

Coalescence temperature = 299°K

*
Results from total lineshape analysis.

logloA = 14.0 i 0.2
2

[91

16.1 i 0.3 kcal/mole

 

90106:?)

5.40
5.00
4.60
4.20
3.80
3.40
3.00

2.60

 

I
3128

Figure 15.

68

L I I l l
3.32 3.36 ' 3.40 3.44 3.48

103/T °K

Plot of 1n(1/21) against 103/T°K for neat
N,N-dimethyltriChloroacetamide.

 

3.52

 

Table 17.
for the internal rotation about the central C-N bond in
neat N-ethyl-N—methylacetamide.

Experimental data and calculated activation parameters

 

T°K

 

325.7
328.7
331.8
333.1
334.8
337.8
338.2
340.1
340.8
344.2
347.2

349.1

103/T°K

' 3.070

3.042
3.014
3.002
2.987
2.960
2.957
2.940
2.934
2.905
2.880

2.865

31»
T

88C

 

0.0685
0.0543
0.0347
0.0314
0.0250
0.0206
0.0193
0.0173
0.0169
0.0122
0.0092

0.0077

1n(1/21)

1.988
2.220
2.668
2.766
2.997
3.191
3.256
3.362
3.387
3.714
3.994

4.176

*
5v
Hz

15.9
15.9
16.0
15.8
16.2
15.9
16.1
15.6

15.7

 

0.502
0.493
0.500
0.464
0.520
0.470
0.518
0.475

0.503

 

'Ea = 20.8 i 0.5 kcal/mole

#
AG 298

fist =

7.0 i 2.0 eu

18.0 i 0.5 kcal mole

Coalescence temperature = 344°K

*
Results from total lineshape analysis.

10g1oA = 14.8

20.1 i 0.5 Real/mole

 

l... .1 All...“ .

in I'& 1’)

414C)

4‘”)

31K)

3120

2!“)

2A“)

21!)

70

 

 

I I l I I I I

 

2.86 2.90 2.94 2.98 3.02 3.06 3.10
103/T°K

Figure 16. Plot of ln(1/21) against 103/T°K for neat
N-ethyl—N-methylacetamide.

I“

 

IF—

71

Table 18. Experimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
neat Nfinfbutyl-N-methy1acetamide.

 

 

 

 

T°K 103/T°K T* ln(1/21) 8v* pA*
.222... Hz

329.0 3.039 0.0432 2.449 14.7 0.476

'333.8 2.996 0.0284 2.869 15.0 0.470

334.0 2.994 ‘ 0.0295 2.832 14.8 0.480

337.8 2.961 0.0190 3.268 15.1 0.474

338.2 2.957 0.0183 3.310 15.4 0.494
'341.1 2.931 0.0154 3.478
342.6 2.919 0.0134 3.618
345.1 2.898 0.0112 3.798
347.2 2.880 0.0089 4.030
347.8 2.875 0.0083 4.094
352.1 2.840 0.0060 4.421

 

 

163,0A a 14.1 2 0.3

20*... = 17.9 2 0.5 kcal/mole as? = 19.1 1 0.5 kcal/mole

A13:t = 4.1 i 2.0 eu

Ea = 19.7 2 0.5 Real/mole

Coalescence temperature = 341°K

*
Results from total lineshape analysis.

nnlfizlrl

‘16C1

4120>

31K)

33K)

3&X)

2!“)

21K)

 

72

0 CH3

’0-111’

1130’ ‘01121011212 0113

I I l I I

 

2134

Figure 17.

2.88 2.92 2.96 3.00 3.04
103/7°K

Plot of 1n(l/2T) against 103/T°K for neat
anfbutyl-N-methylacetamide.

.1

“uh 'I

W“. 57‘.”
1

73

lineshape analysis of the N-methyl proton resonance. The experimental
data and the calculated activation parameters are tabulated in Table 19.
The logarithm of the rate constant is plotted against 103/T°K in Figure
18. .

N-Isopropyl-N-methylacetamide --- Hindered internal rotation in N-
isopropyl-N-methylacetamide in the neat liquid was studied by total line-
shape analysis of the N-methyl proton resonance. The experimental data f“‘
and calculated activation parameters are tabulated in Table 20. The

logarithm of the rate constant is plotted against 103/T°K in Figure 19.

Resonance Assignments in the Proton
NMR Spectra of Several Tertiary Amides

 

In this study, Eu(f0d)3, tris(l,l,l,2,2,3,3-heptaf1uor0-7,7-dimethy1-
4,6-octanedionato) europium (III), a paramagnetic shift reagent, was used
to assign the proton resonances in substituted amides. Spectra were ob-
tained at 100 MHz at a temperature chosen for each amide to be well below
the coalescence temperature so that the rotational isomers are distin-
guishable. Samples were 0.2 M amide in C014 and increasing amounts of
Eu(fod)3 were added. The chemical shifts relative to TMS were plotted
versus the mole ratio of shift reagent to amide. A linear correlation was
found for each group of protons. A linear least-squares analysis was
applied to each data set to ascertain the chemical shift in the absence of
n=1 n=0

8 ) value for each group of

shift reagent and the AEu (AEu = SCC14 ' C014

protons. The chemical shift in the absence of shift reagent was used to
assign the resonance to the corresponding group of protons.

l-Methyl-Z-pyrrolidinone --- To establish the validity of the method,

 

1-methy1-2-pyrr01idinone was chosen as a model system since the Namethyl

74

Table 19. EXperimental data and calculated activation parameters
for the internal rotation about the central C-N bond in
. neat N-cyclohexyl-Ndmethylacetamide.

 

 

 

 

 

 

1°x 103/1°x 1* 1n(1/21) 6v* pA*
.2251._ Hz

305.1 3.277 0.1439 1.245 11.1 0.457
314.1_ 3.184 0.0506 2.290 11.2 0.447
318.5 3.140 0.0364 2.621 11.1 0.470
320.7 3.118 0.0347 2.667 10.7 0.487
321.8 3.107 0.0304 2.801 10.7 0.485
322.3 3.102 0.0292 2.840 11.1 0.450
324.7 3.080 0.0212 3.159

326.8 3.060 0.0171 3.376

330.1 3.029 0.0124 3.699
'Ea'= 18.9 1 0.5 kcal/mole logloA = 14.1 1 0.3

20*296 = 17.1 i 0.5 kcal/mole 0H3 = 18.3 1 0.5 kcal/mole

AS: = 3.9 i 2.0 cu

Coalescence temperature = 325°K

*
Results from total lineshape analysis.

4420

3!“)

3040

3110

1.8CI

L4!)

IIX)

75

 

 

I I I I I I I

 

 

3.02 3.06 3.10 3.14 3.18 3.22 3.26
103/7°K

Figure 18. Plot of 1n(1/21) against 103/T°K for neat
Necyclohexyl—N-methylacetamide.

Table 20.
for the internal rotation about the central C-N bond in
neat N-isopropyl-N-methylacetamide.

76

Experimental data and calculated activation parameters

 

T°K

 

305.6
314.8
316.7
318.9
320.8
322.3
325.4
326.6

330.8

103/T°K

3.272
3.177
3.157
3.136
3.117
3.102
3.073
3.062

3.023

*
T

88C

 

0.1028
0.0453
0.0414
0.0335
0.0278
0.0233
0.0181
0.0156

0.0104

1n(1/21)

1.581
2.402
2.492
2.704
2.888
3.066
3.319
3.467

3.873

*
8v
Hz

 

11.4
11.5
11.2
11.2
11.3

11.2

 

0.444
0.459
0.441
0.457
0.440

0.448

 

E = 18.1 1 0.5 Real/mole

...:
\I
0
1+

2.0 eu

0.5 kcal/mole

Coalescence temperature = 322°K

*
Results from total lineshape analysis.

log1oA = 13.6 i 0.3

Aflt

17.5 t 0.5 kcal/mole

91111511

4.20

3. 80

3u40

3.00

2.60

2.20

1u80

|.40

77

_ 0 0113

§C%NI
1130’ \c111c1-1312

 

 

I I I I I I. I
3.02 3.06 3.10 3.14 311 8 3 22 3.26

1/1'°1< x103

Figure 19. Plot of ln(1/21) against 103/T°K for neat
N-isopropyl-N—methylacetamide.

78

group is fixed in the gig (to oxygen) position. The proton resonance of
the N-methyl group can be identified even without the addition of the
shift reagent because the resonance appears as a singlet, the only sing-
let in the spectrum. The chemical shifts from the addition of Eu(fod)3,
and the results of the least-squares analysis, are given in Table 21.

As expected the gig-methyl protons were shifted to a greater extent than
the Eggggémethylene protons in solutions containing the amide complexed
with the shift reagent. The AEu value for the gigfmethyl protons is
10.12 ppm and for the Egggggmethylene protons is 5.49 ppm. For the re-
maining amides the resonances of the gigfggagg pair which are shifted the
greater amount are assigned to the gig group.

N,N-Dimethylformamide --- The proton spectrum of N,N-dimethylforma-

 

mide shows three resonances. The formyl proton resonance appears at 7.86
ppm and the two N-methyl protons resonate at 2.93 and 2.81 ppm. The re-
sults from the addition of Eu(f0d)3, and the least-squares analysis, are
tabulated in Table 22. For the uncomplexed amide the chemical shift at
2.81 ppm was assigned to the gisfmethyl protons (AEu = 9.39 ppm) and the
chemical shift at 2.93 ppm to the trans-methyl protons (AEu = 4.04 ppm).

N,N-Diethylformamide --- The proton NMR spectrum of N,N-diethyl-

 

formamide shows five resonances: a singlet at 7.90 ppm from the formyl
proton, two quartets at 3.30 and 3.26 ppm from the N-methylene protons,
and two triplets at 1.19 and 1.10 ppm from the methyl protons. The data
from the addition of Eu(f0d)3 are tabulated in the Table 23 along with
the results of the least-squares analysis. The quartet at 3.30 ppm was
assigned to the gig (to oxygen)-methy1ene proton (AEu = 9.86 ppm) and the
quartet at 3.26 ppm to the-Egang-methylene protons (AEu = 3.87 ppm). The

triplet at 1.19 ppm was assigned to the trans-methyl protons (AEu = 2.48

 

79

Table 21. Proton chemical shiftsa, observed and calculated, in
lemethyl-Z-pyrrolidinone, with increasing amounts of Eu(fod)3.

 

0

§§§ CHa(1)
C--N
/’

(4)H2C CHz(2)

\/\

‘\\

B
N

A
$3

Mole Ratio of Shift Reagent/Amide

 

 

 

 

 

0.00 0.097 0.194 0.291 0.00
8 b 8
Proton Resonance obs calc AEu
(1) 2.76 3.78 4.78 5.75 2.80 i 0.02 10.12 i .08
(2) 3.32 3.87 4.41 4.93 3.34 i 0.01 5.49 i 0.05
(3) 1.98 2.49 2.99 3.48 2.00 i 0.01 5.09 i 0.05
(4) 2.19 3.54 4.85 6.12 2.25 i 0.03 13.33 i 0.12

 

aSpectra'were obtained at 32°C.

bA11 chemical shifts are in ppm from TMS.

80

Table 22. Proton chemical shiftsa, observed and calculated, in
N,N-dimethylformamide with increasing amounts of Eu(fod)3.

 

0 CH3(1)

/

, /C—N\
(3)H CH3(2)

Mole Ratio of Shift Reagent/Amide
0.00 0.084 0.166 0.248 0.330 0.00

 

 

 

 

 

 

 

0 b 6
Proton Resonance obs calc AEu
(1) 2.81 3.65 4.37 5.18 5.97 2.85 i 0.03 9.32 i 0.16
(2) 2.93 3.30 3.60 3.96 430.1 2.95 i 0.02 4.04 i 0.10 1 ,
(3) 7.86 9.09 10.12 11.29 12.43 7.94 i 0.06 13.42 i 0.20 [—7

 

aSpectrawere obtained at 32°C.

bAll chemical shifts are in ppm from TMS.

81

Table 23. Proton chemical shiftsa, observed and calculated, in
N,N—diethylformamide with increasing amounts of Eu(fod)3.

 

 

 

 

 

 

0 CH2(1)-C33(2)
\ /
C'——N
1’ ‘\
(5)H CHz(3)-CH3(4)
Mole Ratio of Shift Reagent/Amide
0.00 0.100 0.200 0.300 0.400 0.0
b
Proton Resonance 6Obs 5calc AEu
(1) 3.30 4.33 5.40 6.34 7.24 3.35 i 0.07 9.68 i 0.27
(2) 1.10 1.72 2.35 2.92 3.46 1.12 i 0.04 5.79 i 0.15
(3) 3.26 3.68 4.11 4.49 4.84 3.26 i 0.03 3.87 i 0.12
(4) 1.19 1.46 1.74 1.98 2.21 1.18 i 0.02 2.48 i 0.08
(5) 7.90 9.29 10.23 12.01 13.23 7.99 i 0.10 13.10 t 0.36

 

aSpectrawere obtained at 32°C.

bA11 chemical shifts are in ppm from TMS.

82
. ppm) and the triplet at 1.10 ppm to the cis-methyl protons (AEu = 5.79

9991) .

§,N-Diisopr0py1formamide --- The proton NMR spectrum of N,N-diiso-
propylformamide shows five resonances: the formyl proton resonates at
8.03 ppm, the N-methine protons resonate at 3.87 and 3.55 ppm, and the
methyl protons resonate at 1.27 and 1.26 ppm. The data from.the addition
of Eu(fod)3 in Table 24 along with the results of the least-squares anal-
ysis. The chemical shift at 3.87 ppm was assigned to the gig (to oxygen)
methine proton (AEu = 8.24 ppm) and the chemical shift at 3.55 ppm was
assigned to the Eragggmethine proton (AEu = 3.07 ppm). The assignment
for the methyl protons is very uncertain because of the proximity of the
resonances. Tentatively, the resonance at 1.27 ppm was assigned to the
Eggggrmethyl protons (AEu = 2.14 ppno and the resonance at 1.26 ppm to
the gigfmethyl proton (AEu = 6.03 ppm).

N,N-Dimethylacetamide --- The proton NMR spectrum.of N,N-dimethyl-
acetamide shows three resonances. The N-methyl protons resonate at 2.99
and 2.85 ppm and the acetyl protons resonate at 1.96 ppm. This amide was
studied by use of two different shift reagents, Eu(fod)3 and tris(l,l,l,-
.2,2,3,3-heptaf1uoro-7,7-dimethyl-4,6-octanedionato) praseodymium (III),
Pr(fod)3. The shift reagent Pr(f0d)3 produces upfield shifts, however the
resultant effect is identical to Eu(fod)3. The results from the least-
squares analysis and the addition of Eu(fod)3 are given in Table 25 and
the results from Pr(fod)3 in Table 26. The resonance at 2.99 ppm was
assigned to the trans-methyl protons (AEu = 5.24 ppm, APr = -9.04 ppno and
the resonance at 2.86 ppm to the gig-methyl protons (AEu = 10.18 ppm,

APr = -16.16 ppm).

 

83

Table 24. Proton chemical shiftsa, observed and calculated, in_
N,N-diisoprOpylformamide with increasing amounts of Eu(fod)3.

 

0 CH(1)-(Cfla)2(2)
‘§§(:-11/’

\
(518/ cn<3>-<cn.)2(4>

Mole Ratio of Shift Reagent/Amide

 

 

 

 

0.00 0.100 0.200 0.300 0.400 0.00 I
5 b 0
Proton Resonance Obs calc AEu
(1) 3.87 4.80 5.60 7.27 8.28 3.96 i 0.02 8.24 i 0.10
(2) 1.26 1.90 2.46 3.07 3.70 1.27 i 0.03 6.03 i 0.10 4
Y! F"
(3) 3.55 3.95 4.24 4.55 4.87 3.62 1 0.01 3.07 1 0.05 "'
(4) 1.27 1.50 1.70 1.93 2.14 1.28 i 0.01 2.14 i 0.03
(5) 8.03 9.18 10.21 11.29 12.42 8.07 i 0.04 10.81 i 0.16

 

aSpectrawere obtained at 32°C.

bAll chemical shifts are in ppm from TMS.

84

Table 25. Proton chemical shiftsa, Observed and calculated, in
N,N-dimethylacetamide with increasing amounts of Eu(f0d)3.

 

0 'CH 1
// 3( )
\\
(3)1130/ 0113(2)

Mole Ratio of Shift Reagent/Amide

 

 

 

 

 

 

 

 

0.00 0.100 0.200 0.300 1555; 5-77’
Proton Resonance 6obsb 5calc AEu
(1) 2.85 3.92 4.94 5.96 2.90 1 0.03 10.18 1 0.02
(2) 2.99 3.50 4.02 4.54 2.97 1 0.005 5.24 1 0.01
(3) 1.96 3.17 4.30 5.45 2.03 1 0.01 11.39 1 0.06 5:75

 

aSpectra‘were obtained at 32°C.

bA11 Chemical shifts are in ppm from TMS.

85

Table 26. Proton chemical shiftsa, observed and calculated, in
N,N-dimethylacetamide with increasing amounts of Pr(fod)3.

 

0 CH 1
//, 3( )

(3183/ \011312)

Mole Ratio of Shift Reagent/Amide

0.00 0.095 0.190 0.285

 

5

 

 

Proton Resonance obs
(1) 2.85 1.32 -0.16 -1.74
(2) 2.99 2.09 1.29 0.38
(3) 1.96 0.34 -l.17 -2.92

0.00

5calc

 

2.87 i 0.03

2.97 i 0.02

H-

2.02 .05

APr

-l7.22 i

0.10

0.09

0.16

 

aSpectrawere obtained at 32°C.

bA11 Chemical shifts are in ppm from TMS.

 

86
N,N-Dimethylcarbamylch10ride —-- The proton spectrum of N,N-dimethyl-

carbamylchloride shows two resonances,at 3.17 and 3.06 ppm,for the N-
methyl protons. The results from the addition of Eu(fod)3 and the least-
squares analysis are given in Table 27. The chemical shift at 3.17 ppm
was assigned to the Eggggfmethyl protons (AEu = 6.18 ppm) and the chemie
cal shift at 3.06 ppm to the gigfmethyl protons (AEu = 11.65 ppm).

N,N-Dimethyltrichloroacetamide --- The proton spectrum of N,N-

 

dimethyltrichloroacetamide shows two resonances,at 3.38 and 3.10 ppm,from
the N-methyl protons. The results from the addition of Eu(fod)3 and the
least-squares analysis are tabulated in Table 28. The resonance at 3.38
was assigned to the Eggngimethyl protons (AEu = 7.99 ppm) and the reso-
nance at 3.10 ppm to the gigfmethyl protons (AEu = 16.63 ppm).

N,N-Dimethyltrifluoroacetamide --- The proton NMR spectrum of N,N-
dimethyltrifluoroacetamide shows two resonances, at 3.13 and 3.02 ppm,
from the N-methyl protons. Each of these resonances is split into quar-
tets due to the long-range coupling with fluorine (I = 1/2). The results
from the addition of Eu(f0d)3 and the least-squares analysis are given in
Table 29. The chemical shift at 3.13 ppm was assigned to the trans-
methyl protons (AEu = 5.12 ppm) and the chemical shift at 3.02 ppm to the
gigfmethyl protons (AEu = 9.38 ppm).

Ethyl-N,N-dimethy1carbamate --- The proton NMR spectrum of ethyl-

 

N,N-dimethy1carbamate shows four resonances. The methylene and methyl
protons of the ethoxy group resonate at 4.18 and 1.32 ppm, respectively.
The N-methyl protons resonate at 2.94 and 2.92 ppm. The results from the
addition of Eu(fod)3 are given in Table 30. The resonances assignments
for the N-methyl protons could not be made with certainty because the

chemical shift (2.0 Hz) between the cis and trans resonances is smaller

 

87

Table 27. Proton chemical shiftsa, observed and calculated, in
N,N-dimethylcarbamylchloride, with increasing amounts of Eu(fod)3.

 

O /CH3(1) ‘
/ \
Cl 033(2)

MOle Ratio of Shift Reagent/Amide

 

 

 

 

 

 

0.00 0.099 0.198 0.297 0.00
8 b 8
Proton Resonance obs calc afiu
(1) 3.06 4.10 5.37 6.43 2.97 i 0.08 11.65 i 0.30
(2) 3.17 3.71 4.38 4.94 3.11 i 0.04 6.18 i 0.10

 

aSpectra‘were obtained at -22°C.

bAll chemical shifts are in ppm from TMS.

 

88

Table 28. Proton chemical shiftsa, observed and calculated, in
N,N—dimethyltrichloroacetamide with increasing amounts of Eu(fod)3.

 

 

0 /CH3(1)

\/

013C \C'H3(2)

Mole Ratio of Shift Reagent/Amide

 

 

 

 

 

0.00 0.097 0.194 0.291 0.00
8 b 8
Proton Resonance obs calc AEu
(l) 3.10 4.75 6.40 7.92 3.18 i 0.07 16.63 i 0.30
(2) 3.38 4.16 4.92 5.68 3.40 i 0.002 7.99 i 0.02

 

 

aSpectra‘were obtained at -22°C.

bAll chemical shifts are in ppm from TMS.

89

Table 29. Proton chemical shiftsa, observed and calculated, in
N,Nedimethyltrifluoroacetamide‘with increasing amounts of Eu(fod)3.

 

0 /CH3(1)

//

'\\
F3C/ 013(2)

Mole Ratio of Shift Reagent/Amide

 

 

 

0.00 0.100 0.200 0.300 0.00
8 b 8
Proton Resonance obs calc
(l) 3.02 3.97 4.92 5.94 2.97 i 0.04
(2) 3.13 3.58 4.09 4.60 3.07 i 0.005

9.38

5.12

AEu

i 0.14

i 0.02

 

8Spectra were obtained at 32°C.

bAll chemical shifts are in ppm from TMS.

 

90

Table 30. Proton chemical shiftsa, observed and calculated, in
ethyl-N,N-dimethylcarbamate with increasing amounts of Eu(fod)3.

 

 

 

 

 

 

 

0 ‘ CH 1
¢§§ ” 3( )
C--N
/ \
(4)H30-(3)H2C0 CH3(2)
Mole Ratio of Shift Reagent/Amide 5537
0.00 0.100 0.200 0.300 0.00
b
Proton Resonance aobs .. 5calc AEu
(1) 2.92 3.89 4.88 5.75 2.97 i 0.06 9.80 i 0.21
(2) 2.94 3.48 4.11 4.66 2.90 i 0.05 6.24 i 0.16 ‘psj
(3) 4.18 5.65 7.12 8.44 4.28 i 0.09 14.55 i 0.30
(4) 1.32 1.68 2.07 2.48 1.28 i 0.01 4.18 i 0.05

 

aSpectrawere run at -22°C.

bAll Chemical shifts are in ppm from TMS.

91
than the error of the analysis. The AEu value for the gi§.(to carbonyl
oxygen) methyl protons is 9.80 ppm and for the Eggggfmethyl protons is
6.24 ppm.

N-Isopropyl-N-methylformamide --- The proton NMR resonance of N-
Isopropyl-N-methylformamide shows eight resonances, four from each rota-
tional isomer. The formyl proton chemical shift is different for each
isomer being 7.97 and 7.84 ppm. The N-methyl protons resonate at 2.78 and
2.67 ppm. The N-methine protons resonate at 4.53 and 3.78 ppm. The methyl
protons of the isopropyl groups resonate at 1.23 and 1.13 ppm. The re-

sults from the addition of Eu(fod)3 and the least-squares analysis are

 

given in Table 31. The resonance at 2.78 ppm.was assigned to the trans
(to oxygen) N-methyl protons (AEu = 4.20 ppm) and the resonance at 2.67
ppm to the gi§_N1methyl protons (AEu = 9.81 ppm). The resonance at

4.53 ppm was assigned to the gi§_(to oxygen) N-methine proton (AEu =
14.14 ppm) and the resonance at 3.78 ppm to the trans N-methine proton
(AEu = 4.14 ppm). The resonance at 1.23 ppm was assigned to the trans:
methyl proton (AEu = 2.62 ppm) of the isopropyl group and the resonance
at 1.13 ppm, to the gigfmethyl protons (AEu = 4.86 ppm) of the is0propy1

group.
Carbon-13 Chemical Shifts of Aliphatic Amides

The carbon-l3 chemical shifts given in this section were obtained at
.a radiofrequency of 25.1 MHz on a Varian HA-lOO NMR spectrometer with
n0:1se-modulated proton decoupling. The chemiCal shifts were initially
rEtferenced to an external sample of 57% enriched carbon-13 methanol and

Converted to the TMS standard by the following relationship:

92

Table 31. Proton chemical shiftsa, observed and calculated, in
N-is0propyl-N-methylformamide with increasing amounts of Eu(fod)3.

 

0\ /CH3(1) 0\ /CH(5)-(CH3)2(6)
/C——N\ c—b / C—N\
(4)11 CH(2)-(CHa)2(3) (8)11 0113(7)

Mole Ratio of Shift Reagent/Amide

 

 

 

 

 

0.00 0.096 0.193 0.289 _Q__(_)_0_
’ 5 b 8
Proton Resonance obs calc AEu

(1) 2.67 3.60 4.57 5.46 2.68 i 0.05 9.81 i 0.21
(2) 3.78 4.16 4.57 4.95 3.77 i 0.02 4.14 i 0.09
(3) 1.23 1.49 1.74 1.99 1.24 i 0.003 2.62 i 0.01
(4) 7.97 9.26 10.64 11.89 7.96 i 0.08 13.82 i 0.35
(5) 4.53 5.76 7.15 8.45 4.43 i 0.06 14.14 i 0.25
(6) 1.13 1.56 2.02 2.49 1.10 i 0.001 4.86 i 0.01
(7) 2.78 3.14 3.56 3.94 2.74 i 0.03 4.20 i 0.15
(8) 7.84 9.06 10.41 11.68 7.76 i 0.05 13.77 i 0.25

 

aSpectra‘were run at 32°C.

bAll chemical shifts are in ppm from TMS.

93
8mg = 50113011 + 49.4 (42)
In order to comply with the accepted convention for proton NMR spectra,
carbon-13 chemical shifts downfield from TMS are positive and upfield
shifts from.TMS are negative. The uncertainty in the carbon-13 chemical

shift measurements is i 0.1 ppm.

 

Time-averaging with a Varian C-1024 computer was employed in some E——7.
cases to increase the signal-to-noise ratio; however, as a result of the ;
rolling baseline discussed in the Experimental Section, the number of i
scans possible was limited. Fortunately, most of the resonances were i 4
detected after a single scan. Some of the carbon-13 spectra were obtained Ewe)

below the ambient temperature so that both rotational isomers could be
distinguished.

Chemical shift assignments for the first several amides in each series
were rather simple to make. Using these systems as a base, along with
chemical shift data available in the literature, assignments were then

made for the rest of the amides.

Monosubstituted Amides

The carbon-13 chemical shifts for fifteen monosubstituted amides are
given in Table 32. The proton NMR spectra of monosubstituted formamides
exhibit two sets of resonances, one from the conformer for which the N-
alkyl substituent is gig (to carbonyl oxygen) and one from the correspond-
ing trans conformer (114). However, one configuration was dominant; its
fraction decreased from 0.92 for N-methylformamide to 0.88 for N-ethyl-

formamide and N-isopropylformamide, and to 0.82 for N-tfbutylformamide.

94

 

.4280 as 8640526. some

. a .u .8 @3988 we coouoo T909280 no somehow: 3 02/330» nowufimod conumoo

.mzH Eoum Ema CH mum nonfizm ~00H50noo

.o.mm “4 68856316 6063 608661. .246

 

 

m.NN
n.0m o.mm
m.-
m.oN n.mm
3.0H w.a~
w.-
n.m~ «.mm
o.oN ¢.mm
m.oH o.m~
m.NN
01m 018
uoosuwumosm
Hzcooumo

 

 

 

3.8m H.2m 4.282 86384206821351-mrz
H.3H m.oN m.~m 6.8m 6.05. muaamumomasuammm-z
0.32 8.0N H.Nm N.wm 8.N82 mousseuooasuam-a-z
m.m~ n.23 1.8na umuaamususeomaasaouaOmH-z
m.m~ n.23 N.Oea sesamuoumasaouaomH-z
w.- n.03 n.262 66388246021660568H-z
m.m2 1.3m 3.4na 66628441355684H2232-2
o.m2 5.3m H.mea 66024864168121231-2
1.32 4.3m 3.Hea 6642486062120m12
1.32 3.mm m.~oe 06224846021208-z
3.4m 1.14. 68688646535212362-2
«.mm 5.142 66.2441356645212062-z
H.8N o.me~ 68388864a68a212302-z
H.8N «.mea 684880004212382-z
n.3m w.m82 measmauooaseuuz-z

8-8 o-N o-u 60-8 no meeea

ucosuwumnam
oowouuez

 

.868388 663533346566868-z use. :4 6.4830426 46648820 me-coeumo .mm afiema

95

In all other monosubstituted amides, only one resonance was observed in
the proton NMR spectrum for each group of protons of the N-alkyl sub-
stituent.

The carbon-13 NMR spectrum of each monosubstituted amide exhibits
only one set of resonances for the N-alkyl substituent. The spectrom-
eter was not able to detect the less abundant configuration in the
formamides.

In N-monosubstituted amides, the preferred configuration has been
shown to be the one in which the N-alkyl substituent is gig to carbonyl
oxygen by a variety of methods including dipole-moment measurements and
infrared, Raman, ultraviolet spectroscopy (for a detailed bibliography
see reference 114). Thus, the carbon-13 resonances of the N-alkyl sub-
stituents in Table 32 are for the configuration in which the substituent

on nitrogen is cis to carbonyl oxygen.

Symmetrically Disubstituted Amides

The carbon-l3 chemical shifts for twenty-four symmetrically N,N-
disubstituted amides are given in Table 33 (N,N-dimethylamides) and Table
34 (N,N-diethylamides, N,N-diisopropylamides, and N,N-di-nfprOpylamides).
In some cases, the spectrum of a particular amide was recorded at tempera-
ture of 0°C 80 that both rotational isomers could be distinguished.

The chemical shift assignment of the N-methyl substituents in di-
methylamides was based on an expected upfield steric shift for the methyl
group gig to the carbonyl oxygen. This expectation was confirmed experi-
mentally for N,N-dimethylformamide, N,N-dimethylacetamide, and N,N-

dimethylcarbamylchlorida by McFarlane (55), who found that the upfield

 

 

96

. . .. 8 .n .8 008.0800 88 8048.808 8.303.800 .80 880.8880 3 0830.808 8808080048 Conumou

.Uoo um 88088.88...qu 0.803 0.380480 .8050 880 .93 80 80580qu 0.803 0.88045

n

.988. 80.3 885 888 0.80 08.8330 8008.880an

 

 

 

 

 

 

8.88 8.88 8.88 8.88 8.888 888888888888888881z.2184288
8.448 8.888 4.88 8.48 8.888 8888884888888888881z.z
4.88 8.88 8.88 8.888 888888888686888888888888812.z
8.88 8.48 4.88 8.888 88828888868682888888888881z.z
8.88 8.88 8.88 8.488 0888888886868288428888812.z
8.88 8.88 8.888 88886888848888888488088812.z
8.88 8.88 8.848 68888686588888842888881z.z
8.88 8.88 8.88 8.88 8.848 888888858884884888uz.z
8.88 8.88 8.88 8.48 8.848 8888888888688848882881z.z
8.88 8.88 8.88 8.88 8.48 8.848 8888888858Lmr848808881z.z
8.8 8.88 8.88 8.48 8.848 80888888886888488088812.z
8.84 8.88 8.88 8.848 88888888888428888812.z
8.88 8.88 8.888 86888888688488888812.z
IWHNI .Ioflwl Iflwol 888 “80.8.8181
018 0.1.0 088888.84
unguaumnfim us0ouwuwn=m
8.889.800 a0wouuaz

 

.808888882808881z.z 0868 88 8880828 88888888 881868888 .88 08884

97

o o o o xfi an ad vmuocmfi m.“

 

000800 88000800 80

00008080 00 0>800808 00808000 0008000

.080 00 00080000 0803 0800000 880

n

.mZB 808m 800 08 080 000800 800800000

 

 

 

 

 

 

8.88 8.88 0.88 0.88 0.m~ 8.88 8.0m

8.88 8.88 8.88 0.88 8.88 8.88

0.08 0.88 0.88 m.m8 8.08

8.08 8.88 8.88 w.m8 8.0m

8.08 «.mw 0.88 0.88

0.888 8.88 m.m8 8.88 8.88

m.m8 8.M8 8.m8 8.88 8.88

0.88 ~.mm w.m8 8.m8 8.08 8.88

0.08 0.88 o.m8 0.08 8.88

0.88 8.88 8.88 m.oq n.88

8.m8 «.ma 8.8m n.88

00080 080 080 00080 080 00080

0-4 0-0 0-4 0-4 0-8 0-8 0-0 0-8
0000080000m 00000800000
88000800 0000808z

8.00H
o.moH

w.Hna
o.m08
o.~oH

N.moH
8.008
n.88H
«.mma
0.08H
0.Noa

o 0.

008800000880080Lmlanlz.z
008008808880080Lmlwalz.z

008000080080880080008Hntz.z
00880000088008000880Iz.z
0080088OMH800800088QIZ.Z

00800888008800080Iz.z
008000000080800885008012.z
0080088000LMI8800080IZ.2
0080000800808800080|z.z
008000000880008nlz.z
0080058088800080Iz.z

 

88888

 

.000830 0000080000080Iz.z 8880088000350 80000 0000 80

8800888 48880888 88-888888 .88 84888

98
carbon-l3 shift of the N-methyl substituents in each of these amides was

.Eifi to the carbonyl oxygen.

The carbon assignments in N-alkyl substituents larger than methyl
were made with the aid of the two lanthanide shift reagents, Eu(fod)3
and Pr(fod)3. The effect of the shift reagent on an amide will be the
same in the carbon-13 spectrum as in the proton spectrum; that is, the
resonance of a gigfitrgng pair which is shifted the greater amount can be Eff“
assigned to the group gig to carbonyl oxygen. The results of the addi-
tion of 0.2 grams of Eu(fod)3 to a five percent by volume solution of
N,N-dijn-propylformamide in carbon tetrachloride and 0.2 grams of Pr(fod)3

T
to a five percent by volume solution of N,N-di-nfprOpylformamide in carbon L ,J

 

tetrachloride are given in Table 35. Eu(fod)3 shifts the resonances
downfield and Pr(fod)3 shifts the resonances upfield. For the EEETEEEEQ
pair<1 to nitrogen, the carbon resonance upfield was shifted to greater
amount and was assigned to the carbon gig to carbonyl oxygen . The same
result was found for the gigfitggns pair 6 to nitrogen; however, for the
‘gig-tgang pair 7 to nitrogen, the downfield resonance was shifted the
greater amount and was assigned to the carbon in the substituent gig to
carbonyl oxygen. The assignments of carbon resonances for the N-alkyl
substituents in the carbon-l3 spectra of the rest of the amides are based
on this experiment.

The carbon-l3 spectrum of N,N-dimethylpivalamide shows a single reso-
nance for the N-methyl carbons. The reason for this is that the coales-

cence temperature is below the freezing point of this amide.

99

.ix “8
%1 1H},
.8

”8|! I1]. 1.1!.1f1L

 

 

 

 

 

 

.029 5080 500 08 080 800800 400800000
0 o o o o o 0 ma
8 88 8 84 8 88 8 88 8 88 8 88 4 48808888 8
. . . . . . . 029
0 84 0 N8 8 88 0 mm 8 00 N 00 AmAwowvsmv 0
. . . . . . 0:9
0 04 N 88 0 ON 0 48 m 08 m 08 40000000 00800 ozv 0
00080 080 880 80080 080 00080

 

 

 

8 48808880888888 8 48888880888082 8 48880888888082

 

. .0088040008000 008800 08 008005800480080Lmn80uz.z mo
000000808800 48380-2 000 800 0000800 80088000 08-008800 no 0005008800 .00 08809

100

Unsymmetrically Disubstituted Amides

The carbon-l3 chemical shifts for eleven unsymmetrically N,N—disub-
stituted amides are given in Table 36. All of the Spectra were obtained
at 0°C so that both rotational isomers could be distinguished. The
assignment of the N-alkyl substituents are based on the results of the
effect of the lanthanide shift reagent on N,N-di-gfpropylformamide.

The carbon-13 NMR spectra of N-ethyl-N-methylpivalamide and N‘Ef
butyl-N-methylpivalamide exhibit only one set of resonances for each set
of N-alkyl substituents. The reason for this observation is that the
coalescence temperature is below the freezing point of each of these
amides. The carbon-13 spectra of Netfbutyl-N-methylformamide and N-E;

butyl-N-methylacetamide also exhibit only one set of resonances for each

N-alkyl substituent. .This may be a result of the coalescence temperature

being below the freezing point in these amides or one of the rotational

isomers may be strongly preferred over the other (49).

 

101

. ... A .0 .H00000000 08 000800 Hm0o0800 80 00008080 00 0>800H08 00808000 0008000

0

.mzH 808m 800 08 080 00mw00 H00H50000

 

 

 

 

 

 

 

 

 

 

m.w~ m.m~ 0.00 0.00
~.mm ~.m~ H.mm H.mm
0.0a 0.0H m.o~ m.o~ 0.0m 0.0m 0.00 0.00
0.0a 0.0a m.o~ w.o~ n.0m H.Nm 5.50 m.mq
0.0a 0.0H w.o~ N.HN m.om 0.Hm ~.n¢ 5.00
0.0H 0.0H N.o~ o.o~ H.0N m.om w.mq m.wq
m.ma w.o~ m.mq «.mq
m.mH N.HN m.~q 8.00
m.ma m.mH N.mq ~.mq
m.NH 0.0H m.Nq 0.00
m.NH m.qH H.0m m.¢0
080 .mmmmm. mmmmmw 080 080 00080 080 Mmmmmw
0-0. 0:0
Hmmamsz

 

 

m.mm m.mm
m.Hm m.Hm
n.0m 8.0m
0.mm 0.0m
m.~m H.0m
m.m~ 0.0m
0.0m N.mN
0.0N m.w~
0.0m 0.0m
«.mm 0.mm
m.wm 0.0m
080 mmmmmw
Awwnumauz

 

000000800000 00w080wz

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088080808880000-2-88058L0rz
00880H0>HQH00008IZIHmusmLmnz
08808880580888800meuzna8uamumrz
00H500000H00008IZIH0000Lmrz
88280808885800-1380;
008000000Hh00maIZIH>008000le
008808800H>000012ia>008000le
0880888>888800mauzu88numuz
m88080808888080-zu88008-z

888amEHomamsumauzu88au8-2

 

08808

 

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102

 

 

8.0m

0.0m

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0.00

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5.058
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0.058
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5.008

00800000080000E|zn800smhwrz
888080808Hmnumenzu88uamumuz
0880888>80880080-2-88028Lmrz
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00800000080000EIZI80000Lmrz
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00800000080000BIZI800080008IZ
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0880888>8088gumenzu88008-2
m8808000888numenzn88sumuz

08808080888sumauzu88000uz

 

08808

 

8.0.00000

.00 08009

DISCUSSION

Hindered Internal Rotation

Total Lineshape Analysis

The only reliable method for extracting kinetic results from NMR {

 

data is by direct comparison of the experimental lineshape with the spec- i ,9
trum calculated using the theoretical lineshape equation. To obtain the

best values of the NMR parameters a curve fitting procedure is required

and this can best be achieved by means of the digital computer. For ex-

change between two sites, the parameters required are: (a) the chemical

shift in the absence of exchange, 6v; (b) the relative populations at sites

A and B, pA and pB; (c) the spin-spin relaxation times in the absence of

exchange, l/T'2A and l/TéB, as measured from the individual linewidths;

and (d) the rate constant for the exchange process 1/21.

The chemical shift in the absence of exchange was initially deter-
mined at a temperature where the exchange process is slow. It was then
introduced. into the lineshape analysis as an adjustable parameter to be
determined at each temperature below the coalescence temperature. For the
amides studied in this research the calculated chemical shift in the ab-
sence of exchange varied unsystematically about the value initially mea-
sured. However, it has been shown (24) that the chemical shifts of each

resonance do change individually with temperature relative to some

103

104

standard, but the chemical shift difference between the two resonances
remains fairly constant over a large temperature range.

The relative populations, and p8, should be exactly 0.5 for

PA
symmetrically disubstituted amides. For the unsymmetrical amides pA may

vary between zero and unity, but should approach 0.5 with increase in

temperature. In practice, this factor changes only slightly with temp

perature from the value measured in the absence of exchange. Gutowsky f—T‘
.gg _l. (29) were able to use the constant value pA = 0.54 over the entire

temperature range covered in the investigation of the barrier of N-methyl-

N-benzylformamide without introducing appreciable error into the rate

constants. In the research described in this thesis, the curve fitting

 

program calculated values of pA and pB at each temperature up to the
coalescence temperature.

The spin-spin relaxation times as measured from the linewidths in
the absence of exchange become relatively unimportant as the temperature
increases and exchange broadens the linewidths. These values have no
particular significance since they include inhomogeneity broadening, and
the rate constants are not appreciably altered if these values are held

constant throughout the entire temperature range studied.
The Frequency Factor in the Arrhenius Equation

The question of what frequency factors might reasonably be expected
in unimolecular reactions is discussed at length in Glasstone, Laidler
and Eyring (115). According to absolute reaction rate theory the normal
expectation is for the frequency factor to lie in the range 1013 to 1014

sec'1 for the gas phase; Kondrat'ev (116) has reached the same conclusion.

105

Drastic exceptions can be expected only for rather unusual molecules
such as those whose activated state may be a triplet electronic state
with the transition back to the singlet ground state highly forbidden.
Smaller departures in the liquid phase could result if the molecular
ground and excited states were quite dissimilar in some important aspect
such as interaction with solvent molecules. However, with amides, even
if there is preferential solvation of one state or the other, it seems
unlikely that the preference should change greatly from amide to amide
(16). Thus, it seems reasonable that amide frequency factors should lie

in the range 1013 to 1014 sec'l.
Rotational Barriers in N,N-Disubstituted Amides

The energy barriers for hindered internal rotation about the C-N
bond in N,N—disubstituted amides is believed to result largely from the
partial double-bond character of this bond. There is a variety of evi-
dence that the resonance structures of Figure I contribute nearly equally
to the resonante hybrid (117,118). However, there is an insufficient
amount of reliable data available to evaluate the substituent effects of
R1, R2, R3 on the rotational barrier, despite the many articles that have
appeared on the subject. Thus, an attempt has been made in this research
to obtain more precise values for a series of N,N-dimethylamides and to
extend the method of analysis to four unsymmetrically N,N-disubstituted
amides. The results are summarized in Tables 37 and 38.

The barrier heights in amides are indicative of the degree of stabil-
ization of the approximately planar ground state relative to the non-

planar activated state. The factors that tend to stabilize the planar

as!

L...

 

 

 

 

 

 

0,-
.08008000 000000088 80000 08 0080080000 003 000080 805808 00 00880000 00008-00040
.08008000 000000088 80000 08 000008000 003 000080 808800 00 00880000 00008-00080
0803 8808 8.888.8 8.088.88 8.088.88 8.088.88 8.088.88 020
888 888.8- 8.080.88 8.088.88 - 8.088.88 0:0
88 8.88 8.88 8.88 88 0.88 8.8888 88.85888888820858928
x803 8808 8.888.8 8.088.88 8.080088 8.080.88 8.088.88 80820
88 8.088.o 8.088.88 8.080.88 8.088.88 8808208 88808088808080088088008080-z.z
x803 8808 8.880.8 8.080.88 8.088.88 0.088.88 8.088.88 0020
08 0.888.8- 8.88 0.088.88 8.088.88 800288 888008088808888088808080-2.z
m 8803 8888 8.83.8 8.08.88 8.38.88 8.03.88 8088.88 820
888 888.0 8.088.88 8.088.88 - 8.080.88 820
08 8.8 8.888.88 8.088.88 8.088.88 88:08 88808800888808580-z.z
8.33 8888 8.8 88.8 8088.88 8.888 .88 8.3.8.88 8.38.88 88-88808588888388885
80803 8808 0.888.8 8.088.88 8.088.88 8.088.88 8.008.88 0:0
80803 8808 8.888.8 8.080.88 8.088.08 8.088.88 8.088.88 80208 88808080888800080-z.z
.000 00 080580000 0805\80ox (88:000u08 0805\8000 008E<
808 800 808 808808 88

 

.000850 0000080000080nz.z 0880088008800 0500 08 00800008 80080008 00800080 800 0800080800 00800>800<

.88 08888

107

0800000 08005080u000 800 00088008000 000000000 00000800000 088000 000 80800 000 080

.088 .000 0088 080 000
mm .*0 0800050800 0090

 

 

 

 

88.0- 88.0- 8.8 8.88 8.88 8.88 8.88 888080808888080-2-888088088-z
88.0- 88.0- 8.8 8.88 8.88 8.88 8.88 888088888880080-z-88xmao8880-2
88.0- 88.0- 8.8 8.88 8.88 8.88 8.88 888080808880080-z-880=880-z
80.0- 08.0- 8 8 0.8 8.0 8 8.08 8.0 8 0.88 8.0 8 8.88 8.0 8 8.08 888080888888080-z-88808-z
00m *0 .00 080588008 080888000 ~8u000u<w 080JH8008 00850
00
000 880 800 8 8 8
, .808858 8808880888888-z.z
08800880085000: 0500 08 00800008 80080008 00800080 800 0800050800 00800>800< .00 08009

108
ground state are: (1) The degree of double-bond character in the C-N

223g. The double-bond character and the bond energy should be maxima
when the oxygen, carbon, and nitrogen atoms of the amide framework are
coplanar. Alternatively, if the carbon and nitrogen sigma bonds have
spa hydridization the framework would be coplanar. This tends to stabi-
lize the coplanar state. Inductive effects may alter the double-bond
character by withdrawing or supplying electrons. Conjugation of the C-N

bond with substituents will also have an effect. (2) Steric effects.

 

Large, rigid substituents tend to force the trigonally hybridized atoms
of the amide framework out of the plane. Repulsive forces increase as
the substituent size increases, but may be relieved somewhat if the sub-
stituents can be distorted or can rotate internally themselves to reduce
their effective size. Westheimer and Mayer (119) have pointed out the
importance of the bending or distortion of bonds in relieving steric
strain. (3) Intermolecular interactions. A substituent group may inter-
act with another molecule, for example, intermolecular hydrogen bonding.
This could cause a variety of effects. The result might be to increase
the effective size of the substituent group and thereby tend to force the
trigonal atoms of the amide framework out of the plane. Alternatively,
the association might cause the double-bond character to increase and
thereby stabilize the planar ground state.

The NMR spectra of N,N-dimethylformamide were analyzed by two dif-
ferent methods: (1) complete neglect of the coupling between the N-methyl
protons and the formyl proton; and (2) the introduction of the coupling
constants into the theoretical lineshape equation. The results from the
second method agree favorably with the results for N,N-dimethylformamide-dl

in which the effect of this coupling is largely removed. The barrier in

 

-.. :r
3...;

’ v -'I‘-.

 

109
N,N-dimethylformamide is considerably higher than in the remainder of the

dimethylamides. The increased height of the barrier may be due to the
effect of intermolecular hydrogen bonding which will stabilize the ground
state (11,25,35) by formation of dimers or polymers.

For N,N-dimethylacetamide, N,N-dimethylcarbamylchloride, N,N-di-
methyltrichloroacetamide, and N,N-dimethylpropionamide (Table 37) the
values of 46* agree with the best recent values within i 0.2 kcal/mole
while E8 and AH; differ by as much as 1.0 kcal/mole, and AS* by as much
as 4.6 eu, even though all were obtained by total lineshape analysis.

These differences are not far from being within the sums of the random

40.1...

errors and probably give a reasonable idea of the accuracy of the activa-
tion parameters determined in this study.

The effect of substituents appears to be, in nearly all cases studied,
a lowering of the barrier to internal rotation. The effects are not
large and separating out the steric, polar and resonance contributions
is difficult (24). Both polar and resonance contributions should be
small and similar for a series of saturated hydrocarbons substituents
(120) and steric factors might therefore be expected to dominate. Larger
substituents, whether on nitrogen or on carbonyl carbon, should tend to
make the ground state more nonplanar and so reduce the barrier. In the
solid state it has been shown that larger groups produce increasing non-
‘planar distortions in substituted amides by a twisting about the C-N
loond (121). Solvent effects on AG:t have been shown to be small so one
tnay be justified in comparing AG¢ for neat liquids (37).

It has been pointed out (27) that AG¢ decreases with the size of the

aliphatic group R in the series RCON(CH3)2. The new values for N,N-di-

.Inethylacetamide and N,N-dimethylpropionamide fit neatly into this group,

110
for which AG* has the values 21.0 kcal/mole (R = H) (25), 18.1 kcal/mole

(R 5 CH3), 17.2 kcal/mole (R = -C2H5), 16.2 kcal/mole (R = -CH(CH3)2)
(122) and 12.2 kcal/mole (R = -C(CH3)3 (27). It was similarly shown in
a study of the series CH3CONR'2 that the barrier decreases with increas-
ing size of R' (28), with AB: = 17.7 kcal/mole (R' = - C2H5), 17.6 kcal/
mole (R' = isobutyl), and 16.2 kcal/mole (R' = isopr0pyl) reported.

In the series of unsymmetrically N,N-disubstituted amides
CH3CON(CH3)R' studied (Table 38) it is found that AG¢ decreases in the
sequence 18.1 kcal/mole (R' = methyl), 18.0 kcal/mole (R' = ethyl), 17.9

kcal/mole (R' nrbutyl), 17.1 kcal/mole (R' = cyclohexyl), and 17.0

kcal/mole (R'
of the steric and inductive substituent constants, E8 and 0* (120), are
given in Table 38 and it is seen that AG$ decreases with increasing
ability to withdraw electrons inductively and with increasing size (ex-
cept for cyclohexyl). Both factors (more negative 0* and more negative

E8 values) would be expected to lead to a decrease in AG:t for substitu-

ents on nitrogen so the results are reasonable; however, one cannot judge

their relative importance. Since values of ES may contain a hypercon-

jugative component, and since the parameters are being used here in a

somewhat different situation than that for which they were derived (120),

any more detailed analysis of the correlations would not be justified.

The values of K and of -AG for the conformational equilibria in

300°
unsymmetrically N,N-disubstituted amides (Table 39) are somewhat lower
than those obtained earlier from peak areas (49), but the errors in each
case are rather large. Substituents decrease A6300, in the same order

that they lead to decreases in the rotational barrier, but the energy

changes are much larger for AG*. There must then be important substituent

Fm“

 

¢
isopropyl); AH and Ea decrease in the same order. Values

 

111

Table 39. Conformer equilibria in unsymmetrically
N,N—disubstituted amides.

 

 

 

Compound K=pA/pB A6300o K(peak areas)a
(cal/mole)

N-Ethyl-N-methylacetamide 1.04b -21 1.04
N-B-Butyl-N-methylace tamide 1.09 -50 1.13 rm"
N-Cy clohexyl-N—me thy lacetami de 1.15 -81 1. 22 I
N—IsoprOpyl-N-methylacetamide 1.25 -131 1.38
3The preferred configuration (A) has the larger alkyl group cis to

carbonyl oxygen (49). ..uj

 

The error in K is a few percent for each method.

effects on the energy of the transition state. These would be expected
to be quite different from those for the ground state since the configura—
tion at nitrogen can be nonplanar as a result of the decreased delocali-

zation of the lone pair.

Resonance Assignments in Tertiary Amides
by Lanthanide-induced Shifts

The use of lanthanide complexes as reagents to induce paramagnetic
shifts in the NMR spectra of polar organic molecules is now well estab-
lished (84-101). The paramagnetic shift arises from the association of
the lanthanide complex with the polar organic substrate and is largely
dominated by dipolar (pseudo-contact) interactions (102,103). The mag-
nitude of the paramagnetic shift is largely determined by the distance of
the given nuclei from the lanthanide ion. Amides are known to protonate

preferentially on the carbonyl oxygen (123), since the nitrogen lone pair

 

112

is extensively delocalized; one would, therefore, expect that the chemi-
cal~shift reagent would be complexed through the lone pairs of electrons
on oxygen and that the induced shifts in the gi§_(to carbonyl oxygen) and
Egagg_N-alky1 substituents would differ.

A linear correlation was found for the chemical shift for each group
of protons in several amides and the mole ratio of shift reagent to amide.
Chemical shifts relative to TMS were plotted against the mmle ratio of

added shift reagent and values of the chemical shift for an equimolar

ratio of shift reagent (5n=1 ) and pure amide (8n:O ) were obtained by
CC14 CCl4
extrapolation. From these, values of AEu(AEu==5n=l ._8n=o ) were calcu-
CCl4 CC14

lated for each group of protons (Table 40). Extrapolation of the lines
to a molar ratio of zero allows assignments to be made for the amide
resonances in the uncomplexed amide (Table 41).

The validity of the method was established by the choice of l-methyl-
2-pyrrolidinone as a model system since the N-methyl group is fixed in
the gig position. As expected, the gi§_methyl protons were shifted to a
greater extent than the Egaggymethylene protons in the solutions con-
taining the complexed amide. For the remaining amides, the resonances of
the gi§f§£§£§_pair shifted the greater amount were assigned to the gig
group.

The assignments of Table 41 for the uncomplexed amides confirm those
previously made by other methods for N,N-dimethylformamide (47,48,50,51,
124), N,N-dimethylacetamide (47,48,50,51,124), N,N-dimethyltrifluoroacet—
amide (ll), N,N-diethylformamide (51), N,N-diisopropylformamide (51), and
N-methyl-N-isopropylformamide (49). The method is rapid, readily appli-

cable to a wide variety of amides and, to the extent of this investiga-

tion, appears to be generally valid. When a single resonance is observed

r11

 

 

113

Table 40. AEu values for several N,N-disdbstituted amides.

 

 

 

0 CH 10.12 0 CH 9.32
§ / 3 \\ / 3
C‘-N C--N
/’ ‘\t z’ \\
‘\. //’
CH;
5.09 9.68
O CH CH 5.79
\ / 2 3
0 CH3 10.18 C--N
§§ .z’ /’ ‘\.
/’ \\
11.39 H3O CH3 5.24 3.87
0 CH3 9.38 8.24
\ /
/’ '\\ 8§§ x”
F3C CH3 5.12 C-'N
1’ "x
10.81 H CH(CH3)2 2.14
0 CH 16.63 3.07
\ / 3
C--N
./’ \\
C13C CH3 7.99 0 CH3 9.81
§§bC Nil’
0 CH3 11.65 / -‘ \
\C__N/ 13.82 H ca(c113)2 2.62
/’ \\
c1 CH3 6.18 4'14
\ / o mucus). 4.86
C-——N‘\‘ 8§§ ‘,/
CH3CH20/ CH3 6.24 /C—N\

 

 

CBoth isomers of CH0N(CH3)(i-03H7) are present in the same solution.

 

Table 41. Proton resonance assignments in some N,N-disubstituted
amides in CClu solution.

114

 

 

Compound

 

N,N—Dimethylformamide

N,N—Dimethylacetamidec

N,N-Dimethyltrifluoroacetamided

N,N-Dimethyltrichloroacetamide
N,N-Dimethylcarbamylchloride
N,N—Diethylformamide

N,1‘\I-Diisopropylformamidee

N-Methyl-N-isopropylformamidef

Assignment of Upfield Resonance of

cis-trans Paira

 

'Cflb

 

cis
cis

cis

cis

 

trans 32

trans cis 32

-c_1_1_2 -c_1_1_ T°Cb

 

32

32

32

-22

 

trans 32

—cy_ -cu(cga)2

 

8The designation "cis" in this table indicates that the upfield resonance
of the cis-trans pair for the indicated group is cis to oxygen in the CClu

solution containing no shift reagent.

bThe temperature was chosen, in each case, to be well below the coalescence
temperature so that the isomers are distinguishable by NMR.

CUse of Pr(fod)3 gave upfield induced shifts but the assignment of the pro-

ton resonances was the same.

din this amide the spin-spin couplings JH—

JH_F(trans) (ll).

eThis result is less certain than the others since the chemical shift between
the methyl protons in the uncomplexed amide (2 1 Hz) is the same order of
magnitude as the error in carrying out the extrapolation.

f

The major isomer (67%) has the N-methyl substituent cis to oxygen (49).

are anomalous in that JH_F(cis) >

 

115

for the cis and trans protons this method can be used to determine
whether the chemical shifts are accidentally equal or whether the amide

is above the coalescence temperature.

Carbon-13 Chemical Shifts of Amides

The major advantage of carbon-13 over proton NMR for structure
studies is in the increased separation of the chemically shifted peaks.
Under normal operating conditions the linewidths in the spectra of the
two nuclei are not very different whereas the shift range for carbon-13
nuclei is about twenty times larger than for protons. Since chemdcal
shifts are sensitive to structural changes, the increased separation of,
chemical shifts for carbon provides a more powerful way of differentiating
proposed structures. The theory relating chemical shifts to structure
is complex and, at present, does not allow quantitative interpretation
of the experimental data. The most useful approach for structural deter-
mination has proved to be a semi-empirical one based on the considerable
body of experimental evidence, and supported in specific applications by
the use of model compounds. The carbon-l3 chemical shifts in fifty mono-
substituted and symmetrically and unsymmetrically disubstituted amides
are given in Tables 32, 33, 34, and 36.

The carbon-13 chemical shifts in amides are to a substantial degree
influenced by inductive, resonance, and steric effects in a manner which
is familiar for a variety of phenomena involving organic compounds.' The
inductive effect of the nitrogen or carbonyl oxygen in amides on the
chemical shifts of the carbons in substituents may be assumed to be inde-

pendent of conformation but dependent on the degree to which each carbon

 

 

116

is substituted. The resonance effect relates to the kinds and stereo-
chemical relationships between pairs of atoms on vicinal carbons and is
assumed to affect only the shifts of the carbons directly involved. This

effect, which has been considered by Grant t al. (57), is expected to

be sensitive to the conformation. Steric effects have been shown to be
very important in various kinds of hydrocarbons and are expected to be
especially sensitive to conformational changes (57). The problem in
sorting out these influences is that with many substitutions a composite
of effects can be expected.

Nevertheless, comparison of the chemical shifts in amides allows
certain generalizations to be drawn. The carbon directly bonded to nitro-
gen is shifted downfield by approximately 1.5 ppm whenever the formyl H
proton is replaced by an alkyl group, probably as a result of an induc-
tive effect which is transmitted by the electrons delocalized in the
central C-N bond. A carbon directly bonded to nitrogen is also shifted
downfield tn; about 9.0 ppm when the hydrogen bonded to nitrogen, as in
a monosubstituted amide, is replaced by a carbon atom. This shift is
almost identical to the negative inductive effect (+9.4 ppm) which is
observed for hydrocarbons. The chemical shift difference between the
carbons directly bonded to nitrogen which are gig and trans to the car-
bonyl oxygen is consistently about 5 ppm for disubstituted formamides and
decreases with the degree or kind of substitution on the carbonyl carbon.
The large chemical shift difference arises from intramolecular electric
and magnetic fields which are produced by the anisotropies of the C=0 and
OC-R (R = H,CH3...) bonds (55). The chemical shift differences between

cis and trans aliphatic carbons get smaller for carbons farther away from

the carbonyl group. This is to be expected, since the anisotropy effect

 

 

117
falls off as the cube of the inverse of the distance from the center of

thehanisotropic group.

,The monosubstituted amides exhibit only one set of carbon resonances
for the N-alkyl substituent. Proton NMR studies,and a variety of other
methods (114), have shown that the preferred configuration or isomer in

monosubstituted amides is the one in which the N-alkyl substituent is

 

cis to the carbonyl oxygen. In most of the disubstituted amides studied Ffimmfi
the internal rotation about the central C-N bond can be slowed down on - l

the NMR time scale by decreasing the temperature so that both rotational

isomers could be observed. However, when the carbonyl carbon is bonded

 

to a iybutyl group, decreasing the temperature to the freezing point _ "J
of the particular pivalamide did not sufficiently slow down the rotation
about the C-N bond so that both isomers could be distinguished.
Assignment of the carbon-l3 chemical shifts for nitrogen substitu-
ents were made with the aid of lanthanide shift reagents. The effect of
the shift reagent in the carbon-13 spectrum of an amide was assumed to be
the same as in the proton NMR spectrum, that is, the carbon is a gig:
‘ggggg pair shifted the greater amount can be assigned to the nitrogen
substituent gig to the carbonyl oxygen. For the<1 and B carbons on

nitrogen in N,N-di-gfpropylformamide the up-field carbon resonance for

 

each gigfggggg pair was shifted the greater amount and was assigned to

the carbon in the nitrogen substituent gig to the carbonyl oxygen. How-

ever, the 7 carbons are reversed, the down-field carbon resonance for

this gigfggggg pair being shifted the larger amount. §
One of the purposes in obtaining the carbon-13 chemical shifts for

a large number of amides was to use the data to derive a set of param-

eters by which the chemical shifts in any amide could be predicted,

118
analogous to the method developed by Grant ggugi. (57) for hydrocarbons.

Howgver, because of the inductive effects of both the nitrogen atom and
the carbonyl group, and the large steric interactions between substitu-

ents, a set of parameters could not be found with any reasonable certainty

for the amides studied.

 

 

 

SUMMARY

 

Nuclear magnetic resonance methods have been employed in a series of F_—§
studies of the molecular structure and internal motions of amides in the
liquid phase.

(1) It has been shown that lanthanide shift reagents provide a re-
liable method of assigning the NMR resonances to the gig_and giggg isos é;fij

mers in disubstituted amides. Assignments have been made for a repre-
sentative series of compounds.

(2) The carbon-13 chemical shifts in fifty monosubstituted and di-
substituted amides have been measured and empirically correlated with
structural effects.

(3) The barriers hindering internal rotation about the central C-N
bond of a series of dimethylamides have been measured. The NMR method
for carrying out these studies has been improved by the digitization of
spectra followed by computer curve fitting of the lineshapes to the NMR
parameters.

(4) Internal rotation about the central C-N bond of a series of
unsymmetrically N,N-disubstituted amides has been studied by the NMR
technique developed in this thesis. The energies of activation have been

related to properties of the substituents.

119

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I“? _a '2

_AIBCKE":

r—‘w

 

 

 

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_— 2"

 

 

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121

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