Metallation, conformational analysis, hydrogen exchange and rearrangement in Amides

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Metallation, conformational analysis, hydrogen exchange and rearrangement in Amides
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xii, 164 leaves : ill. ; 28 cm.
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Murugan, Ramiah, 1956-
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Rearrangements (Chemistry)   ( lcsh )
Conformational analysis   ( lcsh )
Chemistry thesis Ph.D
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Notes

Thesis:
Thesis (Ph.D.)--University of Florida, 1987.
Bibliography:
Bibliography: leaves 155-163.
Statement of Responsibility:
Ramiah Murugan.
General Note:
Typescript.
General Note:
Vita.

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Full Text







METALLATION, CONFORMATIONAL ANALYSIS, HYDROGEN EXCHANGE AND
REARRANGEMENT IN AMIDES











BY





RAMIAH MURUGAN


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN
PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY









UNIVERSITY OF FLORIDA


1987


































To my wife

Sutharchana Devi















ACKNOWLEDGMENTS


I would like to sincerely thank my research director,

Professor A. R. Katritzky, for his advice, guidance,

patience and support through out the last five years. I

would also like to thank Professor W. M. Jones for his

advice, support and blessings during the crucial moments of

life--my marriage.

I would like to thank Professor W. S. Brey, Professor

J. A. Zoltewicz and Dr. R. W. King for their helpful

discussions during the course of this work.

I would also like to thank very much all the members of

our research group past and present of the last five years

for their friendship, support and wonderful discussions.

Special thanks are due to Mr. Jamshed N. Lam, Mr. Steve Cato

and Dr. Gordon Rewcastle for their suggestions after reading

through the manuscript.

I would also like to thank all the faculty and staff of

the Chemistry Department for their understanding and

friendship.

Last, but not least, I would like to thank my family,

especially my daughter, for putting up with me during the

process of writing and typing -his dissertation.


iii













TABLE OF CONTENTS

page
ACKNOWLEDGMENTS........................................ iii

LIST OF TABLES......................................... vii

LIST OF FIGURES............................................... viii

ABSTRACT............................................... xi

CHAPTERS

1. GENERAL INTRODUCTION... ............................. 1

1.1. Structure of the Amide Group.................... 2
1.1.1. Geometry ............................... 2
1.1.2. Rotational Barrier ...................... 4
1.2. Preparation of Amides........................... 5
1.2.1. Acyclic and Cyclic Amides................ 6
1.2.2. Vinylogous Amides........................ 7
1.3. Reactivity of Amides. ........................... 8
1.4. Scope of the Work............................... 10

2. METALLATION OF AMIDES ............................... 11

2.1. Introduction. ................................. 11
2.1.1. Dipole Stabilized Carbanions............ 13
2.1.2. Carboxamido Group Stabilized Carbanions. 13
2.1.3. Synergistic Effects in Stabilization.... 15
2.1.4. Aim of the Work.......................... 16
2.2. Results and Discussion.......................... 16
2.2.1. Preparation of Amides.................... 17
2.2.2. Lithiation of 1,3-Diacylimidazolidines.. 18
2.2.3. Lithiation of 1,3-
Diacylhexahydropyrimidines............... 19
2.2.4. Metallation of 1,3,5-Triacylhexahydro-
sym-triazines............................ 20
2.3. Conclusions..................................... 21
2.4. Experimental.................................... 23
2.4.1. Reagents............................... 23
2.4.2. Preparation of Acyl Derivatives of
Imidazolidine, Hexahydropyrimidine and
Hexahydro-sym-triazine................... 23
2.4.3. Lithiation of the Acyl Derivatives of
Imidasolidines, Hexahydropyrimidines and
Hexahydro-sym-triazines ................. 26
2.4.4. Lithiation of 1,3-Dibenzoylimidazolidine 27
2.4.5. Lithiation of 1,3-
Dibenzoylhexahydropyrimidine............ 28










2.4.6. Lithiation of 1,3-
Dipivaloylhexahydropyrimidine........... 28
2.4.7. Lithiation of 1,3,5-Tribenzoylhexahydro-
sym-triazine. ............................ 29
2.4.8. Lithiation of 1,3,5-
Tripivaloylhexahydro-sym-triazine....... 30

3. CONFORMATIONAL ANALYSIS OF AMIDES.................. 31

3.1. Introduction. ................................. 31
3.1.1. Conformational Analysis Using DNMR..... 32
3.1.2. DNMR Studies of Monoamides............. 33
3.1.3. DNMR Studies of Polyamides............. 34
3.1.4. Aims of the Work........................ 35
3.2. Results and Discussion......................... 35
3.2.1. Conformers of Diamides and Triamides... 36
3.2.2. Model Compounds for Conformational
Analysis of Acyl Derivatives of Cyclic
Secondary Amines-Imidazolidine,
Hexahydropyrimidine and Hexahydro-sym-
triazine ............................... 37
3.2.3. 1,3-Diacylimidazolidines Conformational
Equilibria from H NMR Spectra.......... 43
3.2.4. 1,3-Diacylhexahydropyrimidines 1
Conformational Equilibria from H NMR
Spectra .............................. 46
3.2.5. 1,3,5-Triacylhexahydro-sym-tria ines
Conformational Equilibria from H NMR
Spectra................................. 53
3.2.6. 1,3-Diacyli dazolidines Conformational
Study from C NMR Spectra............. 58
3.2.7. 1,3-Diacylhexahydropyrimidjies
Conformational Study from C NMR
Spectra ................................ 65
3.2.8. 1,3,5-Triacylhexahydro-sym1riazines
Conformational Study from C NMR
Spectra.................................. 72
3.2.9. Kinetic Parameters..................... 72
3.2.10.Mechanism of Conformers Interconversion 81
3.3. Conclusions.................................... 88
3.4. Experimental................................... 89
3.4.1. Instruments and Methods................ 89
3.4.2. Preparation of Amides.................. 90

4. HYDROGEN EXCHANGE IN AMIDES........................ 91

4.1. Introduction .................................. 91
4.1.1. Hydrogen Deuterium Exchange in
4-Pyridones. ............................ 92










4.1.2. Aim of the Work......................... 94
4.2. Results and Discussion........................ 96
4.2.1. Hydrogen Deuterium Exchange in N-(4-
Pyridinoxymethyl)-4-pyridone........... 96
4.2.2. Hydrogen Deuterium Exchange in N-
(Phenoxymethyl)-4-pyridone and
N-(Arylthiomethyl)-4-pyridones..........102
4.2.3. Hydrogen Deuterium Exchange in
2,6-Dimethyl-4-alkoxypyridine Model
Compounds ..............................105
4.2.4. Hydrogen Deuterium Exchange in 4-
Alkoxypyridine Model compounds.......... 106
4.3. Conclusions...................................... 115
4.4. Experimental..................................... 117
4.4.1. Methods and Reagents ...................117
4.4.2. Preparation of N-(4-pyridinoxymethyl)-
4-pyridone.............................. 118
4.4.3. Preparation of N-(Phenoxymethyl)-4-
pyridone and N-(Arylthiomethyl)-4-
pyridone ...............................119
4.4.4. Preparation of N-(4-Pyridylethyl)-
4-pyridone .............................121
4.4.5. Preparation of 2,6-Dimethyl-4-
alkoxypyridines......................... 121
4.4.6. Preparation of 4-Alkoxypyridine Model
Compounds ..............................122

5. REARRANGEMENT IN AMIDES OXYGEN TO NITROGEN
MIGRATION OF ALKYL GROUPS ..........................124

5.1. Introduction...................................124
5.2. Aim of the Work................................ 126
5.3. Results and Discussion........................ 128
5.3.1. Attempted Rearrangements by Chemical
Methods................................ 136
5.3.2. Elucidation of Mechanism of
Rearrangement by Physical Methods...... 137
5.4. Conclusions ................................... 147
5.5. Experimental..................................... 148
5.5.1. Rearrangement of Alkyl Group from
Oxygen to Nitrogen in 4-Pyridones-
General Procedure.......................149
5.5.2. Preparation of the N-(3,5-Dideutero-4-
pyridinoxymethyl)-2,6-dideutero-4-
pyridone ...............................149

6. SUMMARY............................................150

BIBLIOGRAPHY.... .......................................155

BIOGRAPHICAL SKETCH. ................................... 164















LIST OF TABLES


Table page

2.1 Formation of a-Lithio Species of Amides and
their Reaction with Electrophiles................. 22

3.1 1H NMR Chemical Shifts (ppm), J Values (Hz) and
Relative Population (%) of 1,3-
Diacylimidazolidines (3.3) and (3.4).............. 44

3.2 1H NMR Chemical Shifts (ppm) and Relative
Population (%) of 1,3-Diacylhexahydropyrimidines
(3.5) and (3.6)..................................... 52

3.3 1H NMR Chemical Shifts (ppm) and Relative
Population (%) of 1,3,5-Triacylhexahydro-sym-
triazines (3.7) and (3.8) ......................... 57

3.4 13C NMR Chemical Shifts (6 ppm) of 1,3-
Diacylimidazolidines (3.3) and (3.4)............... 63

3.5 13C NMR Chemical Shifts (6 ppm) of 1,3-
Diacylhexahydropyrimidines (3.5) and (3.6)........ 71

3.6 1C NMR Chemical Shifts (6 ppm) of 1,3,5-
Triacylhexahydro-sym-triazines (3.7) and (3.8).... 76

3.7 Relative AGo (kcal mole-1) for Different
Conformers of Amides (3.3 3.8).................. 77

3.8 Coalescence Temperatures and the Free Energies of
Activation of Amides (3.3 3.8).................. 79

5.1 Mass Spectral Data of the Molecular Ions for the
Rearranged Products from (4.3), (4.4) and a
Mixture of (4.3) and (4.4)........................ 147

5.2 Calculated Mass Spectral Peak Intensities and the
Difference Between the Calculated and
Experimental Mass Spectral Peak Intensities....... 148


vii















LIST OF FIGURES


Figure page

1.1 Major Resonance Forms for Amides Showing
Predicted Bond Lengths (A) and Bond Angles....... 3

1.2 Mean Values of Bond Lengths (A) and Angles in
Crystalline Amides .............................. 3

3.1 60 MHz 1H NMR Spectrum of 1,3-
Dibenzoylimidazolidine (in CDC13) at 25C........ 39

3.2 300 MHz IH NMR Spectrum of 1,3-
Dibenzoylimidazolidine (in CDCl3) at -300C....... 40

3.3 60 MHz 1H NMR Spectrum of 1,3-
Dipivaloylimidazolidine (in CDC13) at 25C....... 41

3.4 300 MHz 1H NMR Spectrum of 1,3-
Dipivaloylimidazolidine (in CDC 3) at -700C..... 42

3.5 60 MHz 1H NMR Spectrum of 1,3-
Dibenzoylhexahydropyrimidine (in CDCl3) at 250C. 48

3.6 300 MHz 1H NMR Spectrum of 1,3-
Dibenzoylhexahydropyrimidine (in CDC13) at
-300C ........................................ .. 49

3.7 60 MHz 1H NMR Spectrum of 1,3-
Dipivaloylhexahydropyrimidine (in CDC3 ) at
25C ............................................ 50

3.8 300 MHz 1H NMR Spectrum of 1,3-
Dipivaloylhexahydropyrimidine (in CDC13) at
-1030C ....................................... .. 51

3.9 60 MHz 1H NMR Spectrum of 1,3,5-
Tribenzoylhexahydro-sym-triazine (in CDCl3) at
250C ............................................ 54

3.10 300 MHz 1H NMR Spectrum of 1,3,5-
Tribenzoylhexahydro-sym-triazine (in CDCl3) at
-300C ............................................ 55

3.11 60 MHz H NMR Spectrum of 1,3,5-
Tripivaloylhexahydro-sym-triazine (in CDCl3) at
250C ............................................ 56

viii










3.12 25 MHz 13C NMR Spectrum of 1,3-
Dibenzoylimidazolidine (in CDC13) at 600C........ 59

3.13 75 MHz 13C NMR Spectrum of 1,3-
Dibenzoylimidazolidine (in CDC13) at -30C....... 60

3.14 25 MHz 13C NMR Spectrum of 1,3-
Dipivaloylimidazolidine (in CDC13) at 25C...... 61

3.15 75 MHz 13C NMR Spectrum of 1,3-
Dipivaloylimidazolidine (in CDC13) at -700C..... 62

3.16 25 MHz 13C NMR Spectrum of 1,3-
Dibenzoylhexahydropyrimidine (in CDC13) at 60C. 66

3.17 75 MHz 13C NMR Spectrum of 1,3-
Dibenzoylhexahydropyrimidine (in CDC13) at
-400C ........................................... 67

3.18 25 MHz 13C NMR Spectrum of 1,3-
Dipivaloylhexahydropyrimidine (in CDCl3) at
250C ............................................ 68

3.19 75 MHz 13C NMR Spectrum of 1,3-
Dipivaloylhexahydropyrimidine (in CDC13) at
-1000C .......................................... 69

3.20 25 MHz 13C NMR Spectrum of 1,3,5-
Tribenzoylhexahydro-sym-triazine (in CDC13) at
250C ............................................ 73

3.21 75 MHz 1C NMR Spectrum of 1,3,5-
Tribenzoylhexahydro-sym-triazine (in CDC13) at
-300C........................................... 74

3.22 25 MHz 13C NMR Spectrum of 1,3,5-
Tripivaloylhexahydro-sym-triazine (in CDC 3) at
250C... ............. .....75
4.1 60 MHz H NMR Spectrum of N-(4-
Pyridinoxymethyl)-4-pyridone (in DMSO-d6)....... 98

4.2 60 MHz 1H NMR Spectrum of N-(4-
Pyridinoxymethyl)-4-pyridone (in NaOD-DMSO-d6)
After Exchange at 250C .......................... 99

4.3 60 MHz 1H NMR Spectrum of N-(4-
Pyridinoxymethyl)-4-pyridone (in NaOD-DMSO-d6)
After Exchange at 400C ...................... .... 100










4.4 60 MHz 1H NMR Spectrum of 2-(4-
Pyridinoxy)ethanol (in DMSO-d6)................. 109

4.5 60 MHz H NMR Spectrum of 2-(4-
Pyridinoxy)ethanol (in CD3ONa-CD3OD-DMSO-d6) at
25C ............................................ 110

4.6 60 MHz H NMR Spectrum of 2-(4-
Pyridinoxy)ethanol (in CD ONa-CD3OD-DMSO-d)
After Exchange at 70 C .......................... 111

4.7 60 MHz H NMR Spectrum of 4-(2-
Aminophenoxy)pyridine (in CD3ONa-DMSO-d6)....... 112

4.8 60 MHZ H NMR Spectrum of 4-(2-
Aminophenoxy)pyridine (in CD3ONa-DMSO-d6) After
Exchange at 700C................................ 113

4.9 Base catalyzed Hydrogen Deuterium Exchange in
Different N- and 0-substituted 4-Pyridones...... 116

5.1 Mass Spectrum of (a) N-(4-Pyridinoxymethyl)-
4-pyridone (b) N-(4-Pyridinoxymethyl)-2,6-
dideutero-4-pyridone and (c) N-(3,5-Dideutero-4-
pyridinoxymethyl)-2,6-dideutero-4-pyridone...... 130

5.2 60 MHz H NMR Spectrum of N-(4-
Pyridinoxymethyl)-4-pyridone (in DMSO-d6)....... 132

5.3 60 MHz 1H NMR Spectrum of the Major Product of
Rearrangment Bis(N-4-pyridonyl)methane (in
DMSO-d6)......................................... 133

5.4 60 MHz H NMR Spectrum of the Minor Product
Obtained N-(4-Pyridyl)-4-pyridone (in DMSO-d6) 134

5.5 Mass Spectrum of the Rearranged Product Obtained
from N-(4-Pyridinoxymethyl)-4-pyridone......... 144

5.6 Mass Spectrum of the Rearranged Product Obtained
from N-(3,5-Dideutero-4-pyridinoxymethyl)-2,6-
dideutero-4-pyridone............................ 145

5.7 Mass Spectrum of the Rearranged Product Obtained
from a Mixture of N-(4-Pyridinoxymethyl)-4-
pyridone and N-(3,5-Dideutero-4-
pyridinoxymehtyl)-2,6-dideutero-4-pyridone...... 146










Abstract of Dissertation Presented to the.Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy


METALLATION, CONFORMATIONAL ANALYSIS, REARRANGEMENT AND
HYDROGEN EXCHANGE IN AMIDES

BY

RAMIAH MURUGAN

MAY, 1987

Chairman: Alan R. Katritzky
Major Department: Chemistry


Amides are known to stabilize a carbanion a to the

nitrogen. The synergistic effect of amide groups on

carbanion stability was previously unknown. Thus,

metallation of 1,3-diacylimidazolidines, 1,3-

diacylhexahydropyrimidines and 1,3,5-triacylhexahydro-sym-

triazines has been investigated. The results show no

substantial additional stabilization by the second amide

function. This might be due to steric crowding caused by

the alkyl or aryl group of the acyl units.

Little was known about restricted rotation around C-N

bonds of bis- and trisamides. A H and 1C variable

temperature NMR study of acyl derivatives of cyclic

secondary amines, imidazolidines, hexahydropyrimidines and

hexahydro-sym-triazines, has been performed. Conformer

populations were determined at different temperatures and

their barriers to rotation around the amide C-N bond










calculated from their coalescence temperatures. A possible

mechanism of conformational interconversion was predicted

from the observed spectral change with temperature.

Base catalyzed hydrogen exchange on various N- and 0-

substituted 4-pyridones, including vinylogous amides, was

investigated. Exchange of the 2,6-protons of N-aryloxy- and

N-arylthiomethyl-4-pyridones was five times faster than that

of N-methyl-4-pyridone, indicating the participation of the

heteroatom in the exchange reaction. This participation is

very clear in N-(4-pyridinoxymethyl)-4-pyridone which

exchanges the pyridone 2,6-protons in addition to the

pyridine 3,5-protons at temperatures between 40-500C.

Studies of model compounds such as 2-(4-

pyridinoxymethyl)ethanol, confirm this explanation.

The mechanism for the thermal rearrangement of alkyl

groups from oxygen to nitrogen in 4-pyridones had been

proposed but not proved. A mechanistic study of the thermal

rearrangement using the labelled compound N-(3,5-dideutero-

4-pyridinoxymethyl)-2,6-dideutero-4-pyridone and its

unlabelled analogue was investigated. Based on the product

ratios obtained by mass spectrometry the rearrangement was

found to be intermolecular.


xii
















CHAPTER 1

GENERAL INTRODUCTION



For nearly two centuries the study of amides has proved

to be a rapidly expanding and intriguing area for

investigation. Not only is the amide moiety an important

constituent of many biologically significant compounds but

an understanding of its formation, properties and reactions

is essential for the dynamic growth of peptide chemistry.

This holds great promise for major discoveries essential to

human well being. Besides their biological importance,

amides are of fundamental chemical interest because of their

distinct physical and chemical properties related to the

conjugation between the nitrogen lone pair electrons and the

carbonyl n bond. It is appropriate to survey briefly the

chemistry of amides prior to the discussion of this work.

The following discussion on amides can not hope to be

comprehensive but is intended to give some idea of the

trends observed in this work.









1.1. Structure of the Amide Group


The physical structure of the amide group has been the

subject of much recent work. Reviews on the molecular and
electronic structure [70MI1] and nuclear magnetic resonance
(NMR) properties [70CR517] summarize much of the new

developments including the shape and stereochemistry of the

amide group and spectroscopic properties.





/ \
_N/R2


R1 R3
(1.1)
1.1.1. Geometry


The molecular structure of the amide group in both the

condensed and gaseous phases is fairly well established.
However, several complicating features need to be taken into

consideration when interpreting physical measurements on

these compounds. One of these features is the partial

double bond character of the C(O)-N bond resulting from

delocalization of the nitrogen lone pair electrons into the

n-system of the carbonyl bond. There are two extreme

valence bond forms, zero conjugation (1.2a) and complete

conjugation (1.2b) as shown in Figure 1.1.










0 1200 /R2 O- 120 R2
1.17 1.48 ,', -1.48 1.43 1\.27/ 148
1200 1090 1200 (C N) 1200

R '54 1.01 R 1.54 1.01
1 H 1 H
(1.2a) (1.2b)


Fig. 1.1 Major Resonance Forms for Amides Showing Predicted
Bond Lengths (A) and Bond Angles [79MI1].

X-ray diffraction studies of crystalline amides [70MI1]
show a fairly constant geometry for the amide group. All the
heavy atoms of the amide functionality are essentially in a
plane. The mean values of the bond lengths and the bond

angles are given in (1.3) (Figure 1.2).





0 1210 R2
1.24 141.44
S1.34
124 0- N) 1150
/ 1150
R. H 0.95
1.52
(1.3)
Fig. 1.2 Mean Values of Bond Lengths (A) and Angles in
Crystalline Amides [79MI1].

The gas phase microwave and electron diffraction

studies [70MI1], [74BCSJ631] compared to X-ray diffraction









studies of crystalline amides show that the bond angles
remain essentially the same but the C-0 bond length is
reduced to 1.19-1.20 A with concomitant lengthening of the
C-N bond to 1.36-1.37 A. This implies that there is a
greater contribution from structure (1.2a) in the gas phase
than in the solid phase.


1.1.2. Rotational Barrier


One of the most fundamental concepts in all
investigations of structure is conformational analysis. In
amides the consequence of partial double-bond character is
the existence of conformational isomers (1.4) and (1.5),
arising from the lack of free rotation about the C(O)-N
bond. The existence of these isomers has been established
by dipole moment measurement [64JAM337], infrared and Raman
spectroscopic studies [70MI1] and by nuclear magnetic
resonance (NMR).






H R ___ 2
S \ / \/R

1 R R H
2
cis (E) trans (Z)
(1.4) (1.5)






5



Amides have been intensively studied by NMR [70CR517].

Though most of these studies have dealt with rotational

isomerization about the C(O)-N bond, considerable attention

has also been given to chemical shifts, J couplings, proton

exchange and association of the amides.

The effect of solvent and concentration on the free

energy of activation (barrier) has been studied [65JCP3320,

70MI1]. The barrier increased with increase in solvent

polarity. Similarly, the barrier is also increased with

concentration. In both cases the ground state was expected

to be stabilized by polar solvents and by dipole-dipole

association at higher concentrations.

The effect on the barrier of substituents on both the

nitrogen and the carbonyl group has been investigated and a

number of references are available [70CR517, 74JAM2260,

67JAM4300].



1.2. Preparation of Amides



The amide linkage can be assembled in several ways, and

this is reflected in the variety of methods available for

the synthesis of amides [70MI1], their cyclic analogues the

lactams [70MI1], and the vinylogous amides the 4-pyridones

[74MI1].










1.2.1. Acyclic and Cyclic Amides



The most common synthetic pathway for amides themselves

is that of bond formation between a carbonyl-carbon atom and

an amino-nitrogen atom, and this is achieved by treatment of

either ammonia or a primary or a secondary amine with an

acylating agent. This yields a primary, secondary, or

tertiary amide, respectively. The other common pathway for

amide formation is the introduction of a carbonyl group into

an unsaturated amino compound, for example, partial

hydration of either a nitrile or an imidoyl derivative,

producing the primary or secondary amide, respectively. The

imidoyl derivative itself can in principle be obtained by

alkylation of the nitrile. Methods of N-alkyl or N-aryl

bond formation (other than direct replacement of the amido-

H) principally require rearrangements such as in the Schmidt

or Beckmann reactions. Synthesis of amides by formation of

the bond between an alkyl or aryl group and the carbonyl

carbon atom is the most difficult method to achieve and

requires more specific reagents such as ketenes,

isocyanates, and isocyanides. Neither direct oxidation nor

reduction of suitable precursors has wide applicability in

amide synthesis.

The synthesis of lactams (cyclic amides) generally

follows the same procedures as for acyclic amides except









where special factors such as ring size and ease of reaction

are concerned. Further modification of the parent lactam can

be achieved by alkylation of the nitrogen atom, and

sometimes of the carbon a to the carbonyl group using

conditions similar to those for acyclic amide alkylation.

The new method available for a-metallation of amides (a to

nitrogen) followed by electrophilic addition giving a-

electrophile substituted amides (84CR471]. This was one of

the methods used for preparing a-metalloamine synthetic

equivalents (for further details see Chapter 2).


1.2.2. Vinylogous Amides


4-Pyridones can be prepared in two basic ways, by ring

closure reactions and by the transformation of other ring

compounds. For example, in the latter case 4-pyrones can be

transformed into 4-pyridones just by treating the

corresponding 4-pyrones with the required amines. However,

the ring closure reactions yielding 4-pyridones have many

more possibilities, using (i) a triketone or a ketoaldehyde

and ammonia [65JAM3186], (ii) 0-diketones and aromatic

Schiff bases [69BCSJ1357], (iii) 0-diketones and

benzonitrile [69BCSJ2389], (iv) di-1-propynyl ketone and

primary amines [60A1409], and (v) primary and secondary

enamines, prepared from ethyl acetoacetate or B-diketones,

with diketene [69M132].









1.3. Reactivity of Amides


Since all three atoms in the 0-C-N chain are

potentially reactive, amides become versatile organic

compounds. This is primarily due to the delocalization of

the t electrons along the 0-C-N chain. Hence the ground-

state structure of amide is a hybrid of the two resonance

forms (1.6a) and (1.6b). Although versatility often means

complexity, simplification here can be achieved by

recognizing that the majority of reactions of amides fall

into two classes. The first involves nucleophilic attack by

the oxygen atom, or occasionally by the nitrogen atom, on

either positively charged or neutral electrophilic reagents.

Here the resonance form (1.6b) is usually the more

appropriate reactive species. The second, and less common

process involves nucleophilic addition to the amide carbonyl

group of (1.6a). Most other reactions of amides such as

dehydration, elimination, deamination, etc., are sequential

to these two processes.




0

R- --- R --C
1 1

-- ----R-

3 3


(1.6a)


(1.6b)









Because of n electron delocalization along the 0-C-N

chain, the electrophilic properties of the carbonyl carbon

atom are attenuated. Hence amides are much less reactive

electrophiles than carboxylic esters. Enhancement of

polarization of the C=O bond, either by protonation or

complexation of the oxygen atom, is usually necessary before

such a reaction can occur. Since amides are relatively weak

bases, with protonation and complexation occurring on oxygen,

they should also be feeble nucleophiles with oxygen being

the most nucleophilic site. This explains why neutral

amides react only with the more powerful electrophilic

reagents forming, initially, the O-substituted derivative.

Although N-substituted compounds are commonly isolated from

reaction mixtures, they usually originate from

rearrangements of the 0-substituted derivatives and

therefore represent the thermodynamically stable product

[70MIll (for further details see chapter 5). Direct N-

substitution occurs only in special circumstances, either

when powerful electrophilic species such as diazoalkanes are

used or when the reaction is carried out in the presence of

a strong base, which creates the amide conjugate base as the

reactive species. For example, N-alkylation is conveniently

achieved by treating a lactam successively with sodium

hydride and alkyl halide in benzene.

Amides usually get hydrolyzed with N-acyl bond fission

to regenerate the parent carbo ylic -cid and an amine.









Since the initial step requires nucleophilic addition to the

carbonyl group and with amines particularly amine anions,

being poor leaving groups, it is not surprising that this

reaction is often sluggish. Water itself, for example, is

virtually inert and many amides can be recrystallized from

this solvent. Hydrolysis is much easier either under

alkaline conditions, where the more powerful HO nucleophile

is available, or under acidic conditions, where the

protonation of the substrate assists both nucleophilic

attack by H20 and expulsion of the amine. Hydrolysis of

lactams is similar, but is generally easier because of ring

strain. However, the vinylogous amide, 4-pyridone, is quite

stable under the acidic or basic conditions normally used

for the hydrolysis of amides [74MI1].





1.4. Scope of the Work



The main objectives of this work were (i) to

investigate the synergistic effect of amide functionality on

the a-metallation of amides, (ii) to study the

conformational behavior equilibriaa and kinetics) of bis-

and tris-amides using NMR spectroscopy, (iii) to elucidate

the mechanism of the rearrangement of an imidate to an amide

in a vinylogous amide, and (iv) to study the base catalyzed

hydrogen deuterium exchange bn hho;i r of different 0- and N-

substituted vinylogous amides.















CHAPTER 2

METALLATION OF AMIDES



2.1. Introduction

The main aim of the metallation studies on amides was

for the transformation of amines into a-substituted amines.

Therefore, before discussing the objective of this work a

brief discussion is given on the different methods available

for amine transformation. The classical methods for the

preparation and transformation of amines employ (i)

nucleophilic substitution by nitrogen, (ii) nucleophilic

addition to a carbon nitrogen double bond and (iii) radical

substitution at carbon adjacent to nitrogen (scheme 2.1).

+
-+ N Y -N-E





-N- --- Cu Nu




y.
S -- C --- N--- --- -C-N-

Scheme 2.1

Recent methods however, involve introducing an

activating group on the nitrogen atom and then removing the

proton from the carbon adjacent to the nitrogen using metal









alkyls, to generate a-metallo amine synthetic equivalents.

Then addition of an electrophile followed by the removal of

activating group gives the a-electrophile substituted amine

(scheme 2.2).


H

-- C- N-H
I I


H
RM
- C-N-Z Z _
I I


Scheme 2.2


E
Z


FN +L
SE
-- L ..--- IN J -( __ _


-
C_ N _
I I



+ -
N -_--Z
[ I




+ -
-C =N -Z
I (

(2.1)
i "


A number of species have been used as activating

groups. In a recent review [84CR471] the different groups

used for this transformation have been discussed, it also

compares the advantages and disadvantages of the different

groups which arise either from the initial introduction of

the group or removal after the transformation. In all the

groups discussed the main idea behind the activation was

their ability to stabilize an .-carbanion by dipole


stabilization.









2.1.1. Dipole Stabilized Carbanions


A carbanion is considered to be dipole stabilized when

it is adjacent to a heteroatom which is the positive end of

a dipole (Scheme 2.2). The group Z can provide

stabilization in the transition state leading to (2.1) by

complexation with the metal of the base, by dipole

stabilization, and/or by resonance delocalization [84CR471].

Mechanism of metalation has been reviewed [84CR471]. In

addition to dipole stabilization in the lithiation of amides

by IR observation in a stopped-flow spectrometer and syn

substitution indicate, complexation plays a major role in

the reaction (see (2.2) of Scheme 2.3).



2.1.2. Carboxamido Group Stabilized Carbanions



The observation that dipole stabilized carbanions (2.2)

can be formed from amides and undergo electrophilic

substitution as shown in scheme 2.3 led to investigations of

a number of systems in which the activating function Z

contains a carbonyl group [78CR275, 79AG(E)239, 81JOC4108].

The carbonyl group should be efficiently added to and

cleaved from the amine, as well as being resistant to

nucleophilic addition by the alkyl lithium base which is

required to form the carbanionic intermediate (2.2).










0 H


RC CHR

CH2R


0 E


QC WCHR

CH2R


sec-BuLi
--


Scheme 2.3


0--- i


R/CG CHR
CH2R

R


O Li


I
RC + .CHR

CH2R
(2.2)


Various substituents adjacent to the carbonyl have been

investigated in different amides and the 1,1-diethylpropyl

group was found to be the best of all those considered

[81JOC4316].

Although a great number of acyl groups have been used in

the transformation of amines into a-substituted amines,

there has been no investigation of whether there is

synergistic effect, with two or more amide functionalities,

on the stabilization of a carbanion.


E +
<------








2.1.3. Synergistic Effects in Stabilization


Dipole stabilized anions of type RR'C NR"-X=Y are known
for a wide variety of groups X=Y [77TL1839,78CR275].
However, little is known about the synergistic effect of
such stabilization in derivatives of type RC-(NR'-X=Y)2.
Recently, it has been demonstrated [83T4133] that lithiation
of methylenebispyrazoles, to give metallated derivatives of
type (2.3), is indeed somewhat easier than the formation of
the corresponding monocyclic analogues (2.4).


CHLi

rN
1 1


(2.3)


CH2Li


(2.4a)


CH2Li


(2.4b)


The classic example of the synergistic effect has been
the work on cyclohexane-1,3-dithiane which has been greatly
exploited in organic synthesis [74JAM1807, 77JAM8262,
65AG(E)1075, 65AG(E)1077, 75JOC231].









2.1.4. Aim of the Work


The aim was to study the a-metallation behavior of a
series of compounds containing the structural feature
CH2(NRCOR )2'


2.2. Results and Discussion


Cyclic 1,3-diamines and 1,3,5-triamines were chosen as
the starting compounds and the acyl derivatives of these
compounds were prepared for the study. The acyl unit was
either a benzoyl or a pivaloyl group.
The compounds prepared for the study were 1,3-
dibenzoylimidazolidine (2.5), 1,3-dipivaloylimidazolidine

(2.6), 1,3-dibenzoylhexahydropyrimidine (2.7), 1,3-
dipivaloylhexahydropyrimidine (2.8), 1,3,5-
tribenzoylhexahydro-sym-triazine (2.9) and 1,3,5-
tripivaloylhexahydro-sym-triazine (2.10).


NCOR


CO
R

(2.5) R = C 6H

(2.6) R = C(CH3)3


NCOR


ROCN I NCOR


KN) K=N
CO CO
R R

(2.7) R = C6H5 (2.9) R = C6H5

(2.8) R = C(CH3)3 (2.10) R = C(CH3)3









2-.2.1. Preparation of Amides


Compounds (2.5) and (2.6) were prepared from 1,2-

ethylene diamine, formalin and benzoyl chloride or pivaloyl

chloride, respectively (scheme 2.4) Compounds (2.7) and

(2.8) were prepared from 1,3-propanediamine, formalin and

benzoyl chloride or pivaloyl chloride, respectively (scheme

2.4). However, compounds (2.9) and (2.10) were prepared

from sym-trioxane and benzonitrile or pivalonitrile,
respectively (scheme 2.5).


H2N(CH2)nNH2 + HCHO
2 (C9Z 2


Scheme 2.4


0 0

^O


+ RCN


1.NaOH
2.RCOC1


H 0


(CH2 ) NCOR

nN


(2.5) R = C6H5 n=2

(2.6) R = C(CH3)3 n=2

(2.7) R = C6H5 n=3

(2.8) R = C(CH3)3 n=3


ROCN NCOR

N
CO
R


Scheme 2.5


(2.9) R = C6H5

(2.10) R = C(CH3)3









2.2.2. Lithiation of 1,3-Diacylimidazolidines



Lithiation of (2.5) with lithium diisopropylamide (LDA)

in tetrahydrofuran (THF) at -780C gave a dark brown solution

of a carbanion. Under most conditions, the very reactive

carbanion reacted with more of (2.5) acting as an

electrophile, to give the self condensation product (2.11).

Formation of (2.11) was also confirmed by the appearance of

a ketone carbonyl signal in the 1C NMR. Addition of LDA to

a mixture of (2.5) and an electrophile in THF still gave

(2.11). Use of benzaldehyde or para-tolualdehyde as the

electrophile gave the corresponding benzyl alcohol, along

with starting material, as observed from H and 13C NMR

spectra, and dimers of compound (2.5) as observed from mass

spectrometry.

The use of amide (2.6) was an attempt to avoid self

condensation by the introduction of steric crowding around

the carbonyl group. However, this method failed as (2.6)

did not react with LDA, even at 0C. Evidently the tert-

butyl group increased the steric crowding not only around

the carbonyl but also around the C-2 carbon, thus hindering

the approach of the base LDA to the C-2 hydrogen. Similar

explanations have also been given for 1,4-dibenzoyl-2,3-

dimethylquinoxalines not reacting with LDA [84JCS(Pl)1949].









Use of less nucleophilic tert-butyllithium for

deprotonation instead of LDA gave the expected product after

treatment with an electrophile. By this procedure the C-2

methylated compound (2.12) was obtained from compound (2.5)

using methyl iodide as the electrophile. However, the

expected product was not isolated with compound (2.6) and

methyl iodide.



NCOC6H5 (2.11) E = COC6H5

E (2.12) E = CH3
CO
C6H5



2.2.3. Lithiation of 1,3-Diacylhexahydropyrimidines


Lithiation of (2.7) with LDA also afforded a dark

colored solution indicating the formation of the carbanion,

but again on work-up only the self condensation product

(2.13) was obtained. The same product (2.13) was also

obtained on adding LDA to a solution of (2.7) and an

electrophile in THF. When benzaldehyde or para-tolualdehyde

was used as the electrophile, the corresponding benzyl

alcohol was formed, as evidenced by 1H and 1C NMR. Use of

tert-butyllithium as the base with compound (2.7) gave the

expected carbanion which was trapped with D2O to give

(2.14).









A more stable carbanion was obtained from (2.8) in THF

at -780C with LDA, and this was trapped with D20 to give

(2.15), and with methyl iodide to give (2.16). The 1H NMR

spectrum of (2.15) showed four signals with chemical shifts

identical to the starting material (2.8), however, the

intensity of the signal for the C-2 proton was one fourth of

the signal for the C-4 and C-6 protons.



(2.13) R = C6H5 E = COC6H5

NCOR (2.14) R = C6H5 E = D
(2.15) R = C(CH3)3 E = D

CO (2.16) R = C(CH3)3 E = CH3
R




2.2.4. Metallation of 1,3,5-Triacylhexahydro-sym-triazines


Low solubility of (2.9) in THF and DME below 0C

prevented the usual procedure with LDA as base. However,

LDA addition at 25C gave the carbanion which was trapped

with D20 to give (2.17). Metallation under polar conditions

was attempted, but treatment of (2.9) with dimsyl sodium

followed by an electrophile gave only starting material

back.









Lithiation of (2.10) in THF at -780C with LDA gave the

carbanion, which was trapped with D20 to give (2.18).




ROCN NCOR (2.17) R = C6H E = D

'N E (2.18) R = C(CH3)3 E = D
CO
R


2.3. Conclusions


Lithiation studies with 1,3-diacylimidazolidines, 1,3-

diacylhexahydropyrimidines and 1,3,5-triacylhexahydro-sym-

triazines (Table 2.1) indicate that no substantial

additional increase in carbanion stability occurs as a

result of the introduction of the second dipolar stabilizing

group. This might be due to the fact that the conformer

favoring the double stabilization was not the predominant

conformer (discussed in chapter 3). Within the amides

studied the carbanions derived from the benzoyl derivatives

(2.5), (2.7) and (2.9) were found to be less stable, with

(2.5) being the least. However, carbanions derived from

pivaloyl derivatives (2.8) and (2.10) were found to be more

stable with (2.8) being the most. This might have been due

to the increase in steric crowding around the amide C=O

bonds, making them less susceptible for nucleophilic









Table 2.1 Formation of a-Lithio Species of Amides and
their Reaction with Electrophiles


Amide



(2.5)



(2.5)



(2.7)



(2.7)



(2.8)



(2.8)



(2.9)



(2.10)


Electrophile


CH3I


Procedure



A



B



A



B



A



A


Product Yield (%)


(2.11)b



(2.12)



(2.13)b



(2.14)



(2.15)



(2.16)



(2.17)



(2.18)


a For a description of General Procedure A and B see

Experimental.

b The same product was also obtained in presence of


electrophiles.


D20



D20



CH3I



D2O
D20


D20









addition reactions. In addition, ring size was also found

to be a factor. Five-membered ring was found to be more

influenced by the steric nature of the acyl unit than the

six-membered.


2.4. Experimental



Melting points were recorded on a Bristoline hot-stage

microscope and were uncorrected. Proton NMR spectra were

recorded on a Varian EM 360L spectrometer using internal

Me4Si as the reference. IR spectra were obtained on a

Perkin-Elmer 283 B spectrophotometer.



2.4.1. Reagents



Tetrahydrofuran (THF) was refluxed over and distilled

from sodium benzophenone ketyl. n-BuLi (1.6 M in hexane)

and t-BuLi (1.7 M in pentane) were standardised by titration

[80CC87]. Diisopropylamine was refluxed over and distilled

from CaH2.

2.4.2. Preparation of Acyl Derivatives of Imidazolidines,
Hexahydropyrimidines and Hexahydro-sym-triazines


Preparation of 1,3-dibenzoylimidazolidine (2.5):

Ethylenediamine (5 g, 0.08 M) and formaldehyde (6 g,

37% solution) at 1000C were stirred for 0.5 h. The viscous









colorless liquid was then kept at 55-600C. Benzoyl chloride

(20 g, 0.14 M) was added dropwise over 30 min. while

maintaining a pH of 8-10 with 10% NaOH solution (75 mL).

The mixture was then stirred for 1 h at 250C. The 1,3-

dibenzoylimidazolidine separated out and was recrystallized

from acetone (10 g, 40%) as plates, m.p. 140C
-1
(lit.[73JHC439], m.p. 140-1410C); vmax (CHBr3) 1628 cm ; 6

(CDC13) 3.88 (4 H, s), 5.19 (2 H, s), and 7.55 (10 H, s).



Preparation of 1,3-dipivaloylimidazolidine (2.6):

Ethylenediamine (5 g, 0.08 M), formaldehyde (6 g, 37%

solution) and water (50 mL) were stirred at 1000C for 1 h.

To the viscous colorless liquid, aqueous sodium hydroxide

(32 g, 0.8 M in 120 mL of water) was added. The mixture was

cooled to between -10 and -200C and trimethylacetyl chloride

(19.2 g, 0.16 M) added dropwise. After further stirring for

1 h, 1,3-dipivaloylimidazolidine (9 g, 50%), separated. The

crude solid was washed with water and recrystallized from

chloroform, to give prisms, m.p. 1410C (Found: C, 64.7; H,

10.1; N, 11.4. C13H24N202 requires C, 64.9; H, 10.1; N,
-1
11.6%); max (CHBr3) 1620 cm ; 6 (CDC13) 1.28 (18 H, s),

3.79 (4 H, s), and 5.05 (2 H, s).



Preparation of 1,3-dibenzoylhexahydropyrimidine (2.7):

Propane-1,3-diamine (15 g, 0.20 M), water (150 mL) and

formaldehyde (37 -, 5 mL .i i: --' for 2 h.

Sodium hydroxide (2.5 M, 75 mL) was added at 25C and then









benzoyl chloride (28 g, 0.20 M) dropwise. After stirring

for another 1 h, 1,3-dibenzoylhexahydropyrimidine (15 g,

25%) separated. Crystallization from ether-chloroform gave

plates, m.p. 94-950C (lit.[67AJC1643], m.p. 92-960C); vmax

(CHBr3)1625 cm-1; 6 (CDCl3) 1.80 (2 H, m), 3.81 (4 H, t, J=6

Hz), 5.17 (2 H, s) and 7.40 (10 H, s).



Preparation of 1,3-dipivaloylhexahydropyrimidine (2.8):

Propane-1,3-diamine (3.7 g, 0.05 M), formaldehyde (37%

25 mL) and water (150 mL) were stirred at 100C for 2h.

Sodium hydroxide (2.5 M, 70 mL) was added at -400C, and then

pivaloyl chloride (12.1 g, 0.10 M) was added dropwise.

After stirring the mixture at 0C for 1 h, column

chromtography (alumina and ether) gave 1,3-

dipivaloylhexahydropyrimidine (4 g, 32%) which crystallized

as plates (from ether), m.p. 1150C (Found: C, 65.9; H,

10.0; N, 11.3. C14H26N202 requires C, 66.1; H, 10.3; N,
-1
11.0%); vmax (CHBr3) 1620 cm 1; (CDCl3) 1.28 (18 H, s),

1.70 (2 H, m), 3.76 (4 H, t, J=6 Hz) and 5.31 (2 H, s).



Preparation of 1,3,5-tribenzoylhexahydro-sym-triazine (2.9):

Compound (2.9) was prepared as reported earlier

[76S467], it formed prisms from ether-chloroform, m.p. 221C
-1
(lit. [76S467], m.p. 220-2230C); v (CHBr3) 1640 cm ; 6

(CDC13) 5.30 (6 H, s), 7.40 (15 H, s).









Preparation of 1,3,5-tripivaloylhexahydro-sym-triazine

(2.10):

Compound (2.10) was prepared following the literature

method [76S467] for (2.9) in 45% yield as needles from

ether-chloroform, m.p. 134-1360C (Found: C, 63.8; H, 9.9; N,

12.2. C18H33303 requires C, 63.7; H, 9.7; N, 12.3 %);
-1
V ma(CHBr3) 1630 cm 1; 6 (CDCl3) 1.35 (27 H, s) and 5.40 (6

H, s).



2.4.3. Lithiation of the Acyl Derivatives of Imidazolidines,
Hexahydropyrimidines and Hexahydro-sym-triazines


General procedure A:

LDA (1 mmol) was prepared by adding dropwise di-

isopropylamine (0.14 mL, 1 mmol) to n-butyllithium in hexane

(1 mmol) at -200C under nitrogen. Stirring was continued

until it became cloudy (0.5 h) and then dry THF (5 mL) was

added. The mixture was then cooled to -780C and the amide

(1 mmol) in dry THF (10 mL) was added. Stirring was

continued for 1 h at -780C and for 10 h more at 200C. Water

(1 mL) was added, and solvents removed at 40-500C/20 mmHg.

The residue in methylene chloride (50 mL) was washed with

saturated aqueous NaCl (10 mL) and water (10 mL) and then

dried (sodium sulphate) and evaporated at 40-500C/20 mmHg.

Products were separated by column chromatography.









General procedure B:

Similar to procedure A except that t-butyllithium was

used instead of LDA.



2.4.4. Lithiation of 1,3-Dibenzoylimidazolidine



1,3-Dibenzoyl-2-methylimidazolidine (2.12):

Following procedure B using 1,3-dibenzoylimidazolidine

(2.5) with methyl iodide as the electrophile gave 1,3-

dibenzoyl-2-methylimidazolidine (2.12) (20%) as needles from

CHC13, m.p. 1500C (Found: C, 73.3; H, 6.3; N, 9.4.

C18H18N202 requires C, 73.5; H, 6.1; N, 9.5 %); max(CHBr3)

1625 cm-1; 6 (CDCl3) 8.30-7.30 (10 H, m), 5.50 (1 H, q, J=5

Hz), 4.35-3.60 (4 H, m) and 1.38 (3 H, d, J=5 Hz).



1,2,3-Tribenzoylimidazolidine (2.11):

1,3-Dibenzoylimidazolidine (2.5) following procedure A

self condensed to give 1,2,3-tribenzoylimidazolidine (2.11)

(90%) as needles from CHCl3, m.p. 2280C (Found: C, 74.8, H,

5.5; N, 7.4. C24H20N203 requires C, 75.0; H, 5.2; N, 7.3 %);
-l1
vmax (CHBr3) 1710, 1625 cm-1; 6 (CDCl3) 8.50-7.30 (15 H, m),
4.00 (4 H, s) and C-2 proton not observed.









2.4.5. Lithiation of 1,3-Dibenzoylhexahydropyrimidine


2-Deuterio-1,3-dibenzoylhexahydropyrimidine (2.14):

1,3-Dibenzoyl-hexahydropyrimidine (2.7) following

procedure B with D20 as the electrophile gave 2-deuterio-

1,3-dibenzoylhexahydropyrimidine (2.14) (20%) as needles

from ether, m.p. 950C (Found: C, 73.2; H, 5.8; N, 9.1.

C18H17DN202 requires C, 73.2; H, 5.8; N, 9.5); vmax (CHBr)3

1625 cm-1; 6 (CDCl3) 7.40 (10 H, s), 5.17 (1 H, s), 3.81 (4

H, t J=6 Hz), and 1.80 (2 H, m).


1,2,3-Tribenzoylhexahydropyrimidine (2.13):

1,3-Dibenzoylhexahydropyrimidine (2.7) following

procedure A without any electrophile gave 1,2,3-

tribenzoylhexahydropyrimidine (2.13) (80%) as needles from

CHCl3, m.p. 225C (Found: C, 75.2; H, 5.7; N, 7.0.

C25H22N203 requires C, 75.4; H, 5.5; N, 7.0 %); vmax (CHBr3)
1715, 1628 cm-1; 6 (CDCl3) 8.20-7.25 (15 H, m), 4.05-3.30 (4

H, m), 1.90-1.30 (2 H, m) and C-2 proton not observed.


2.4.6. Lithiation of 1,3-Dipivaloylhexahydropyrimidine



2-Deuterio-l,3-dipivaloylhexahydropyrimidine (2.15):

1,3-Dipivaloylhexahydropyrimidine (2.8) following

procedure A with DO as electrophile gave 2-deuterio-1,3-

dipivaloylhexahydrcupyrimidin- .1'- .i as plates from









CH2C12, m.p. 115-1160C (Found: C, 65.8; H, 10.1; N, 10.8.

C14H25DN202 requires C, 65.9; H, 9.8; N, 11.0 %); vmax

(CHBr3) 1620 cm-1; 6 (CDCl3) 5.25 (1 H, s), 3.75 (4 H, t,

J=6 Hz), 1.67 (2 H, m) and 1.26 (18 H, s).



1,3-Dipivaloyl-2-methylhexahydropyrimidine (2.16):

1,3-Dipivaloylhexahydropyrimidine (2.8) following

procedure A with methyl iodide as the electrophile gave 1,3-

dipivaloyl-2-methylhexahydropyrimidine (2.16) (80% based on

recovery of starting material) as needles from CHCl3, m.p.

1250C (Found: C, 67.5; H, 10.6; N, 10.3. C15H28N202 requires
-1
C, 67.2; H, 10.4; N, 10.4 %); vmax (CHBr3) 1630 cm 1; 6

(CDC13) 6.90 (1 H, q, J-6 Hz), 4.40-3.40 (4 H, m), 2.00-1.40

(2 H, m), 1.29 (18 H, s) and 1.18 (3 H, d, J=6 Hz).



2.4.7. Lithiation of 1,3,5-Tribenzoylhexahydro-sym-triazine



2-Deuterio-1,3,5-tribenzoylhexahydro-sym-triazine (2.17):

1,3,5-Tribenzoyl-hexahydro-sym-triazine (2.9) following

procedure A, but with addition of LDA to (2.9) in THF at

25C, with D20 as the electrophile gave 2-deuterio-1,3,5-

tribenzoylhexahydro-sym-triazine (2.17) (65%) as plates from

CHCl3, m.p. 2210C (Found: C, 72.1; H, 5.3; N, 10.3.

C24 20DN 03 requires C, 72.0; H, 5.0; N, 10.5 %);
-1
vmax(CHBr3) 1640 cm 1; 6 (CDC1,) 7.54 (15 H, s) and 5.40 (5

H, s).









2.4.8. Lithiation of 1,3,5-Tripivaloylhexahydro-sym-
triazine


2-Deuterio-l,3,5-tripivaloylhexahydro-sym-triazine (2.18):

1,3,5-Tripivaloylhexahydro-sym-triazine (2.10)

following procedure A with D20 as the electrophile gave 2-

deuterio-1,3,5-tripivaloylhexahydro-sym-triazine (2.18)

(85%) as plates from CHCl3, m.p. 1350C (Found: C, 63.4; H,

9.6; N, 12.2. C18H32DN303 requires C, 63.5; H, 9.4; N, 12.3
-1
%); V ma(CHBr3) 1630 cm 1; (CDC13) 5.40 (5 H, s) and 1.35

(27 H, s).















CHAPTER 3

CONFORMATIONAL ANALYSIS OF AMIDES



3.1. Introduction



During the last two decades, NMR spectroscopy has

developed into one of the most valuable techniques for

investigating molecular structure and stereochemistry. Not

only can NMR give the extent of equilibrium between

different conformers but can also yield information about

the dynamic behavior of the different conformers at various

temperatures. This is referred to as dynamic nuclear

magnetic resonance (DNMR). The barrier heights or the free

energy of activation of dynamic processes amenable to this

technique conveniently extend just from the border line of

20-25 kcal mole- below which compounds become too unstable

to be isolated, to about 5-6 kcal mole-1. Restricted

rotation about the C(O)-N bond in amides is the classical

example of a rate process that can be studied by DNMR.

Activation parameters can be obtained to a greater

accuracy using total line shape analysis. However, a great

number of references are available indicating that the









coalescence temperature has been used to obtain the free

energy of activation.


3.1.1. Conformational Analysis Using DNMR


Though DNMR has been used to study all types of

compounds like substituted ethanes, amides, carbamates,

thioamides, nitrosoamines, nitriles, aldehydes and ketones,

only amides will be discussed here.

Resonance theory describes the electronic structure of

amides as a hybrid of (3.1a) and (3.1b) suggesting a certain

amount of double-bond character for the C(O)-N bond, and

thus there is a concomitant increase of the rotational

barrier over that in pure single bonds. There is a chance
"t
to observe the rate process by DNMR because R and R reside

in different magnetic environments (R being more shielded

than R ) [63JAM3728] in the fixed structure (3.1) but are

time-averaged on rapid rotation. This prediction was first

confirmed for dimethylformamide and dimethylacetamide

[55JCP1363].







/ /
N-R" R RN---R'


R" R"


(3.1a)


(3.1b)









3.1.2. DNMR Studies on Monoamides


Of the total number of DNMR studies done on amides, the

major portion has been on monoamides. Initial studies on

dimethylformamide from different groups showed barriers from

6.3-28.2 kcal mole-, which was later attributed to factors

like solvent, concentration, temperature and long range

coupling in addition to instrumental errors. However, using

high field and high resolution instruments with specified

solvent and specified concentration, the difficulties are

overcome. For determination of an accurate value for the

free energy of activation, the total line shape analysis

method has always been used.

A great deal of work has been done on the effect of

substituents (both on the nitrogen and on the carbonyl

group), solvent, and concentration on the barrier. In

certain cases stable amide conformers have been isolated in

pure form [66TL4593], such as in the case of (3.2) where a

severe steric interaction raises the barrier by an

additional amount (30-32 kcal mole- ).


H C CH2C6H5 HC6H H C
32 6 5 H5 6CJ
C(CH3) N C(CH3)3

(CH3) 3C / C (H C)3 C C

C(CH3)3 C(CH3)3


(3.2a)


(3.2b)









3.1.3. DNMR Studies on Polyamides



Restriction of rotation about the C(O)-N bond of amides

has been the subject of intensive study, and the structural

influences on the equilibria and kinetics of the syn-anti

interconversion are well understood for monoamides (scheme

3.1) [68MI1]. However, the same wealth of information is

not available for polyamides. Conformational properties of

polyamides have been obtained from NMR studies of the

conformation of model diamides derived from trans-1,2-

cyclohexane carboxylic acid and different aliphatic amines

[72MM197], and piperazine or N,N'-dimethylethylenediamine

and aliphatic or aromatic carboxylic acids (69MM154].

Signals for the different conformational isomers in diamides

have been assigned using paramagnetic shifts induced by

Eu(fod)3 complexes [72JOC3434].










R 0 N- C

R" R R' R


Scheme 3.1









Indeed, the investigation of DNMR spectra involving

more than two different species has been relatively limited.

NMR investigation of thiophene-2,5-dicarboxaldehyde has been

done in liquid crystals (72JCS(P2)755]. Rotational

isomerism of N,N'-dimethyl-a,w-bis(benzoylamino)alkanes

[84JCS(P2)1089] and 1,3,5-trinitrosohexahydro-l,3,5-triazine

[69RC1687] has been studied using variable temperature 1H

NMR spectroscopy. Stereoisomerization of N,N'-diacetyl-

N,N'-dimethylhydrazine using variable temperature H NMR

spectroscopy has also been studied and a discussion about

the mechanism of stereoisomerisation was given (75GCI569].



3.1.4. Aims of the work



The goals of this work were (i) to elucidate the

equilibria on some cyclic model systems of bis- and tris-

amides, (ii) to calculate the rotational barriers and (iii)

to deduce the mechanism of rotation based on the spectral

behavior at various temperatures.



3.2. Results and Discussion


The model systems chosen for the bis-amide studies were

1,3-diacylimidazolidines (3.3) and (3.4) and 1,3-

diacylhexahydropyrimidines (3.5) and (3.6). For the tris-

amide studies it .-as 1,3, -t J i c-:; :, 7!ydro-sym-triazines

(3.7) and (3.8).










ROCN COR





ROCN NCOR




R
CO

ROC NCOR
ROCN NCOR


(3.3) R = C6H5

(3.4) R = C(CH3)3



(3.5) R = C6H5

(3.6) R = C(CH3)3






(3.7) R = C6H5

(3.8) R = C(CH3)3


3.2.1. Conformers of Diamides and Triamides


A single amide bond can exhibit two conformations.

Similarly two amide bonds together can exhibit four

conformations and three amide bonds together can exhibit

eight conformations. However, on deriving these amides by

acylating cyclic di- and triamines (keeping the acyl groups

the same) some of the conformers become indistinguishable.

For example, in compounds (3.3), (.3.4) (3.5) and (3.6)

although there are four possible conformers only three are

distinguishable. Furthermore, for compounds (3.7) and (3.8)

of the eight possible conformers, only two of them are

distinguishable. The indistinguishable conformers are

referred to as topomers [71, 3I'- .









Distinguishing the different conformers experimentally

(in this case using NMR) was not an easy task. To diagnose

this, model compounds were developed to assign chemical

shifts to the different conformations of the compounds (3.3-

3.8).



3.2.2. Model Compounds for Conformational Analysis of Acyl
Derivatives of Cyclic Secondary Amines Imidazolidine,
Hexahydropyrimidine and Hexahydro-sym-triazine


On investigating the different conformers of all the

compounds, the methylene group between the two nitrogen

atoms was found to be either between the two carbonyl

oxygens, or between the R groups of the acyl units or

between one carbonyl oxygen and one R group of the acyl

unit. Although it was known already that the N-alkyl group

syn to the carbonyl is always more shielded than when it is

anti [63JAM3728], model compounds were still used for the

signal assignments.

Since pivaloyl and benzoyl derivatives of amines were

used, comparison was done with similar model systems.

1,3,3-Trimethyl-2-piperidone (3.9) showed the N-methyl

(necessarily syn to the carbonyl) at delta 3.00 ppm








[75CJC1682]. By analogy, the syn-methyl in N,N-
dimethylpivalamide (3.10) has been assigned to the signal at

2.96 ppm and the anti-methyl to the signal at 3.21 ppm in

the 1H NMR spectrum obtained at -400C.


CH3


k 3CH 3


(3.9)


(3.11)


T0


H C/ CH
3 C H3


(3.10)

(3.12)

(3.13)

(3.14)


R = C(CH3)3

R = C6H5

R = H

R = CH3


In the phenyl series, the model compound N-methyl-

1,2,3,4-tetrahydro-2-isoquinolone (3.11) showed the

(necessarily syn) N-CH3 signal at delta 3.20 ppm [82T539].

N,N-Dimethylbenzamide (3.12) at -26.60C in CH2Br2 showed

signals at delta 3.38 and 3.53 ppm for the N-CH3 protons

[62JPC540] and in comparison with (3.11), the signal at

delta 3.38 ppm was -ssigned t- nmethyl i yn to the carbonyl.
















O


m
<-4
U
0
U

















-4
a,


C










o
N

I
*--4
1-1





0



*>-1
r--


1-4
N
C

a)







r-


0



.0C

(U








'bK


SCj


0








O
0

C-




































































144 44 V


u u




a- C,-
0 1 x
: )=o


44 L






4-4
r^
U"







in
4-1 S


C


- r-I


41













0
























4.J
m
1-
U

















a)
U





C
r-l




N

*4
*-
-r4
0
N
C
-Q




I-4

o
0



4-,




a




N
S
S U
0 0
0 f^
"-1
















-0



4.)












-14

0
C
*r



*c




.,-4


>-1
0


--4


-1-

0
.O
N




*4-




























z
-,4
,-"
































N
0
r-l


a
i



























0 I"
_'0 <^1


LI
3=
U

U


>0
,0 U
Y)






4-Z

0


4n
U
co)























O 0 C






u 00 u


CO co


-4




U






r-I





O
N






C-
r*-









V-
rcI




-*-1
fz 0






-r-











<-i



.^ 0
r










In the case of 1C spectra the signals were assigned to

different conformers by referring to model compounds (3.13),

(3.14) and particularly (3.12), in which the N-methyl

carbons syn to the carbonyl group had been always shielded

(31.1, 34.5, 35.2 ppm, respectively) compared to the anti N-

methyl carbons (36.2, 37.5, 38.9 ppm, respectively) [78MI1].

In addition, the intensity and the number of signals were

also used for the signal assignments.

An interesting feature of these results from the model

systems considered both for proton and carbon, is that

groups syn to the carbonyl oxygen are always shielded over

the groups anti to it.



3.2.31 1,3-Diacylimidazolidines Conformational Equilibria
from H NMR Spectra


At 250C for compound (3.3) (figure 3.1) and for (3.4)

(figure 3.3), a 2H singlet for 2-CH2 and a 4H singlet for

4,5-C2H4 were observed, which demonstrated rapid rotation

about both amide links (Table 3.1). As the temperature was

lowered, these peaks broadened and split and, below -300C

for (3.3) (figure 3.2) and below -80C for (3.4) (figure

3.4), separate signals were observed for each of the three

conformers (Table 3.1). In addition to the above, (3.3)

shows signals for the phenyl protons at 7.56 ppm as a broad

singlet and (3.4) for the t-Bu at 1.28 ppm as a singlet. On














OU
0
4-4


O\


o\
0
-H


irl













-4
0


a)













N

-4
a


4-1

0q












0) 0
N






3 -


















--1
S-





E0
-U1
-m



E m
a-


a)


w'a



-4r




'ca
















E-1
e-4











E-(


co
I *
0
en


I I I O0

U) 0U) 4.)


o0
o LA
co o









e0 0*
Ln

I r-




o n
o to

S *o


-4 0
in i


MI- 0
,-4


\0
I-


U) U)


Sa
N -N

r*o r-1


M
I *
en


0

9


a(



a

N 4-J 0

( 1-4 u)
4 ) 0) 3

S4J> 4 UNN

V-4 U) 3
m 3 : 4
0 0 0



-4O 4-




0 10 r.
M 4-4
4 a O





1 ( in 3
II ('a C :
o
C1 E>. (0
4 1



4) 0) O-4
3o a U) w




a0 LJ 0
s S ) 'a *











SC 0C >
*) *H 4- 4-4 H
4- 4 N 4
II >4'



*u E 0





(n a U)








-1 C) wU 4.E
4-1 N 4-I *
.0 M4

4 E-4



02 5o
-o 4 U) -)



Sa a


-II oE u
C 0





---H r- U)
uc >-i '

r-4 -H O )
Ql U 4- > LL
*- C ITS

r U j-) O -
E C i-i c r


Soia 0


I I I-

U) U) 4g


co en
0, 0

M r



in

m


.Q
0
0
-1 *



0


'a U
u L )
U Ln 0
0o CN m
I









cooling, these peaks broaden and reappear respectively as a

multiple near 7.50 ppm for (3.3) and as three singlets at

1.31, 1.28 and 1.24 ppm for (3.4).

Comparing the model compounds for chemical shift

assignment in conformers (a), (b), and (c) (scheme 3.2) of

(3.3) and (3.4), we expect the 2-CH2 protons to be at

highest field in (a) where they are syn to both carbonyls

and at lowest field in (c) where they are anti to both

carbonyls. Conversely, conformer (a) should show a singlet

at lower field for the 4,5-C2H4 protons than the singlet for

(c). In the unsymmetrical conformer (b), the 4,5-C2H

protons should display an AA'XX' pattern, with the chemical

shift for A nearer to that of conformer (c) and of X nearer

to conformer (a). The assignments in Table 3.1 followed

these considerations.

The relative proportions of the three conformers

obtained from the relative signal intensities are also shown

in Table 3.1. Those for the 2-CH2 indicate (a):(b):(c) =

3.5:80.0:16.5% for (3.3) and (a):(b):(c) = 27.5:70.0:2.5%

for (3.4). Those for the 4,5-CH2 indicate (a):(b):(c) =

5.3:79.5:15.2% for (3.3) and (a):(b):(c) = 30.8:67.7:1.5%

for (3.4). Since the 2-CH2 signals are separate singlets









for the different conformers, they are considered to be more

reliable for isomer proportion deduction than the 4,5-CH2

signals, for which the singlet for the conformers (a) and

(c) overlaps with the AA'XX' double triplets from conformer

(b).

Rationalizing our results it seems that in the

equilibrium for (3.3) at -300C, conformer (b) was favored

over (a) by 1.51 kcal mole-1 and over (c) by 0.76 kcal
-i
mole However, for (3.4) at -700C, conformer (b) was
-l
favored over (a) by 0.35 kcal mole- and over (c) by 1.28
-I
kcal mole1.



3.2.4. 1,3-Diacylhexahydropyrimidines Conformational
Equilibria from H NMR Spectra


At 250C compounds (3.5) (figure 3.5) and (3.6) (figure

3.7), showed a 2H singlet for the 2-CH2 protons, which

demonstrates that, just as for (3.3) and (3.4), rapid

rotation occurs about both amide links (Table 3.2). At low

temperatures for (3.5) (figure 3.6) the peaks broaden and

split and at -300C separate signals were observed for each

of the three conformers. However, for (3.6) (figure 3.8) at

-1030C separate signals were seen only for two conformers.









Signal assignments were based on model compounds

discussed earlier. The C5 protons gave an additional signal

around 1.9 ppm. The assignments of Table 3.2 follow these

considerations. For example the assignments for the 2-CH2

protons of (3.5) and (3.6) are as follows; at -300C, (3.5)

showed three signals for the 2-CH2 protons. Using the rule

derived from model compounds that protons syn to the

carbonyl oxygen were shielded, the one to the lowest field

was assigned to (3.5c), the one to the highest field to

(3.5a), and the middle one to (3.5b) (scheme 3.3). On

similar grounds, of the two signals observed for compound

(3.6), the most intense signal was assigned to (3.6b) and

the remaining one being at higher field than that of (3.6b),

was assigned to (3.6a). Assignments for the C4-C6 protons

were made similarly (Table 3.2).

Relative signal intensities and the isomer proportions

from the 2-CH2 signals are shown in Table 3.2. For (3.5),

(a):(b):(c) = 39.7:53.3:7.0% and for (3.6), (a):(b):(c) =

8:92:0%. From the 4,6-CH2 signals, it was not possible to

derive conformer proportions because of additional coupling

to the 5-CH2, and overlapping of signals.





















e-
U





-,-
C

0.1-4




0





>4
.1-


*4










>9
o
















4-)
u
(0

x
4,























c








1-4
C)





























L.w
f ''


L)




U




ca u
u
Lr)
*o f






























































4-4

uu







LO







ca;





44 L

Lf
g>


Va

0



'

o 3
I-4




r)


-


M

u
r-I
U






0





10
*l


L*


-e




0
x


-4
>4
hl


0
N



.Q.
4J

*-4











a
o








lC)
I

o
( .


. -.




































































O
C')


CV)



U
0







O




co
e n


c0 U


Sl
U

0





0

-4

04

















-4
*M








o



-4
0
*-


















u
a





a-a



0

r-

(0








<


- M






































U




c)


0

0
Cu
ff


n


,C..
U






Q





u z


co C-
c3n

3


0)
Lrr


u-4

*"-











r*4

O
Q,


a















EO
0



E3













mU
0l
rc














00
o o
--1 r-4



r -
E --







0 0

(N ( N
(N

U
S-
in -

0 m


I
r-4

U









41
ol
t-














0
-4

0




P4
O
0












4 -


0




r-4










r-4
-4 --4
za
(U
























CO-4
*H
C


a-




4JlU


0
0
I *
co
,-4


ae r






(N
-












44
v o









co


C)

,* 0
-- -






0
0




e 4-
CO >




,. r-

m m


o 0

4r- co


0


O
0 00
U U
I -
- -4

^, ,o ~
---- ~- r-1







oo o
C
04 --














0 0
0, -
0


(M
N(




U -
I o r-
N r-4l
*



: a
C 0



e c -
o 0
u u


04 n3( r
S U Ln o
E o (N I
E-H I


t -,

1M*-


>1
+a
4-)
*- (I
I N >
C EW -4





,4
4 .) .) -4
4I o ul ,-



-
In 04E







'a "a 0
N-1 )

M 04 4) 0
4J
SA) & 4




40 1 0 0

a 4) ( '
--E CL




0 fu .0
4 ) 04-


,-4 ( n t
r_ W 0


w 0 C E4


4-) ri 40
to 4
-, C l
-4 "4 In

WII c 0 O


S.-4 I 01

) 4-) U)






-I C O)
-, 0 U*,-4i I
CO 0 in 4- l

-- U ( 01


\ Qi 3 01 4



4 Co m O
-a iU




a0 044) rn
r-4 4-) ) -r- 0




4 O


0 --a 0 v 0





-. *a-4C 3 u
4 r'1 0 C 4-






m to M *
0 4- *- 0


II 'a dI 0 -
in E 0 'a


my)








The equilibrium at -300C for (3.5) favored conformer
-l
(b) over (a) by 0.14 kcal mole- and conformer (b) over (c)

by 0.98 kcal mole-1. However, for (3.6), the equilibrium at

-103C favored conformer (b) over (a) by 0.83 kcal mole-.




3.2.5. 1,3,5-Triacylhexahydro-sym-triazines Conformational
Equilibria from H NMR Spectra

At 250C compounds (3.7) (figure 3.9) and (3.8) (figure

3.11) showed a 6H singlet for the three CH2 protons,

demonstrating rapid rotation about all three amide links.

As the temperature was lowered the peaks broadened and

split, and at -300C separate signals were observed for (3.7)

(figure 3.10) for each of the two conformers. However, for

(3.8) only one conformer (x) was observed even for spectra

recorded as low as -1100C using acetone-d6 as the solvent

(Table 3.3) (scheme 3.4).

Signal assignments shown in Table 3.3 follow the same

rules observed for signal assignment for imidazolidines

(3.3) and (3.4), i.e., the protons syn to the carbonyl

oxygen were shielded. The methylene protons for (3.7) at

-30C showed four singlets, of which three signals were of



































03=


O
0



u u

Z--\
U cc


0


*4



N



0I

C>






-I





0
0









L(I
E



a

0:
















to









Ln
N












M "







0D
Co
Sin






S m

0 Qo
-0 'O









H: c 0



ec 0
56


d


TMS


e e
b,c H5C6 d C6H5

e
H5C O6


8 7 6


5 4 3 2 1 0


Fig. 3.10 300 MHz H NMR Spectrum of
hexahydro-sym-triazine (in


1,3,5-Tribenzoyl-
CDC13) at -300C.


d



















































"r'n







Z-\ 0-u






cn L

CL I
C ou,


*f-4
N



I


U,

0





r-i





























0)
U,


Lr-



Z,







o
C(0








u








N-
>o 1







EU
~l m i )































V V
Ln
1-4


--4

0




to
Or
4-4





C
O
0

4-a
















0
04

1-
0 -





a4)
> C




(0
-4-
a) I-



C

a)
-c




E-4
aN

4 C-
i-'



-4 >w

cnI
0


0 >3


U X

u-C


S4
z o











.0
(a


0
-I


.0
0
0
4-
'.0


4-1

-co


u0 o4
M m











i O
L1 0
(14 -


rs u
U Ln 0
o rC1 m
I


4-1
S -


inl


I -4
3


z z

co


1 0

1 Ul U
Q Lt a) o
tn V-4 --4 0
44 1 I-
N > *-1 -1

a *.-' e


E -4 C





03) 0 41
+- C
10C O )


U 0 OJ
-I r-l >









0 0
II w

4-4J >0
C E- (U >







0 0 N
eo








C0 0- 0







S.- 41
C 0 C-











a) --I4 O
11 4J 4
S(U (












S 0 r-.






*1 0 c 4



*U 44 4-)
u w c3 w



















-- to
to *






3 0 (-0 C
m >
















4j -4 a)
1 n V W


I 03 -4 4
C ( 0 H-l
S4-1 c C


II a) a)





C *'4 (U












C~ a X(L


C -
04 o
0
04


LA

rn









equal intensity corresponding to conformer (3.7y). The one

remaining signal was assigned to conformer (3.7x), in which

all methylene protons are identical.

Relative signal intensities and the isomer proportions

from the 2,4,6-CH2 signals are shown in Table 3.3. For

(3.7) (x):(y) = 36.5:63.5% and for (3.8) (x):(y) = 100:0%.

For the equilibrium at -300C (3.7) favored conformer

(y) over (x) by 0.26 kcal mole-1. However, (3.8) was found

to exist exclusively in the (x) conformer.





132.6. 1,3-Diacylimidazolidines Conformational Study from
C NMR Spectra


The 75 MHz spectra of (3.3) (figure 3.12) at 250C were

near coalescence, and showed broadened lines for C-2, C-4

and C-5 which became sharp singlets at 60C; (3.4) (figure

3.14) showed sharp singlets for these carbons at 250C. At -

300C for (3.3) (figure 3.13) and -700C for (3.4) (figure

3.15), signals were seen for the individual conformers

(Table 3.4). The signals were assigned to different

conformers based on the model compounds discussed earlier

(see section 3.2.2).


















O














0
N

r-



















-4
44
0 a
U
















CD
ri-4



,-1
.0











o




O N


















C
,r-I












>1












O -
(U
.e.


(CO ) U

0
cO

B







60



0












m
rn
4'-
u

u
0

o










N


-I
S *a4
o 4





























CN
.-I
.,-






-Q
*r4









O c
in Q
00














Cr
O 0 W
J C
rl a
'"'S s








0
: i-n r

'r^



O
B; \0

3 ;*-
.^ 6-4








61


0












r-4
U

U





C 0







'-4
r-4

00
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-4











r-I
C 9


-4



O




















o
o o







04




Ez
0 Q




0
0 0


















5--4J
r C .
| r ^ S
^ ;z
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j ^






iT =3
X'i '-i
^ o *
^0I
.? T-l


Q) ~ ~ It7
^ "^
*^- fI


cv,




0
0









cc
0d
*Q"


































E









-% U



o


CY-


U







CY,
U










J:


.


U

-4

*4





O-4
0

0
0




-4
















U)
V-4









o
,-4






0
0



U
aJ
*\ Q








rl

w




o




0
^ ~


5


















LA ti in LAI (a


(0 r0
\o in co ON

0 0o 0 0
w m m m m
U ,-4 ,-4 1-


mc0




1-) I U

M m wU
a)' O o -V o

I U M (N (M (r M



U U
. 0 '-4 0 0 \ 0
o
S- 4N 4N C, ri

U




mmmmg
-1 *

r' M mr (V)
-4 .-4 -4 -4


r-
LA *
U Ln









No
C-.
1O
110


CL








00
E--






E o
SC
u


o Ln

co ko0








00
.w *r





o N
'3' tO
o (N)





.0 '3

go r,


.0 '13
c) LA o
I


0 rM

*o





cO cO CO


* *
10 'rn


'o w


en
a)
(N
'.0


go .


in o
N r





-r

en


a



a)

O,

N



a) LA
N


4-1
C

0)







a,
C











rl 0

a> o
E-< 2;

cl0

CO r-


U3 1-4
T-I .-


00 O0
co -1o
\D <>









For compound (3.3) conformers (3.3a), (3.3b) and (3.3c)

showed a total of four signals due to C-4 and C-5 carbons.

Of these, the two intermediate chemical shifts were of equal

intensity and were unambiguously assigned to the conformer

(3.3b). From the rule stated above, that the carbon syn to

the carbonyl oxygen was shielded, the medium intensity peak

at 48.0 ppm was assigned to (3.3a) and the low intensity

peak at 42.8 ppm to (3.3c). (These assignments are in fair

agreement with the conformer populations deduced from the

proton spectra). For the C-2, only two signals were

obtained; the peak of higher intensity was assigned to

(3.3b) and the other one being at a higher field than that

for (3.3b) was assigned to (3.3a). The expected peak for

the least populated isomer (3.3c) was not observed.

Compound (3.4) displayed only three peaks for the 4,5-

carbon atoms: two of equal and high intensity were

unambiguously assigned to (3.4b); the less intense peak at

lower field was assigned to (3.4a), again based on the rule

that the carbon syn to the carbonyl oxygen was shielded.

With conformer (3.4c) being the least populated, (cf proton

spectra) its peaks were not observed. Similarly, for the

C-2 carbon, peaks were found only for (3.4a) and (3.4b).









The 1C chemical shift assignments of the phenyl group

in (3.3) and the t-butyl group in (3.4) were based on the

difference in intensity of the signals, the off-resonance

spectra, and for R=C6H5 comparison with the spectrum of

(3.12). In compound (3.3), the C-2,6 and C-3,5 carbons of

the phenyl ring showed relatively intense signals (doublets

in off-resonance spectrum), and C-l a low intensity signal

(singlet in off-resonance spectrum). In compound (3.4), the

quaternary carbon of C(CH3)3 showed a low intensity signal

at ca. 38 ppm, and the methyl groups gave a very intense

signal at higher field. The lowest field signal in the

spectra of compounds (3.3) and (3.4) was that of the

carbonyl carbons. The low temperature spectrum, of each of

the compound showed three C=O signals of which the two of

equal intensity were assigned to the two carbonyl groups in

conformer (b). The signal due to the least populated

conformer, (a) in (3.3) and (c) in (3.4), was not observed.




3.2.713 1,3-Diacylhexahydropyrimidines Conformational Study
from C NMR Spectra


The 75 MHz spectrum of (3.5) (figure 3.16) at 250C was

near coalescence and showed broadened signals for C-2, C-4,

C-5 and C-6 which became sharp signals at 600C; (3.6)

(figure 3.18) shows sharp signals for the ring carbons at



































Uo








0

U
X;a


0
0
t-4





T--i


-I
*H











0
*4






I
.r-




o









0
c









*l-I













-4)
0
n,








4l-
o



















N
0u
U




mJ


0
-4^


0

1-4


0

1-1


0
0













































































0) >0 '*e




u o

0 0


0.








.0
N



*-
C

*-9




*0







r-1


0
0

*o

I *











U)


-9
o
SC)
)a






















0 en 1



U
o 3







0 n
N0 r

























































c


u



0


O






^^
sr


-I



.4





0





c
*--1








0

r-





>1
.C





0
r-q




o





0.



O -4 -




0 0




m 4J
or







'-4
Tc3







69











U,
CN4

-4



nn





0-
r--









--------- -
1-1

a






o









II
>4






0











0
US











u .41

0
-4








0401
--4

1-4



0o




U0




NL



e-U


U
co
n
















U


>-





CY,

U
en









250C. At -400C signals for the individual conformers

appeared in the spectrum of (3.5) (figure 3.17). However,

for (3.6) at -70C separate signals were seen only for two

conformers as was described above for the 1H spectrum

(figure 3.19).

Signals were assigned by reference to model compounds

as discussed earlier. The C-5 carbon gave an additional

signal around 24.5 ppm. The assignments of Table 3.5 follow

these considerations. An illustration for the C-2 carbons

of (3.5) and (3.6) is as follows; at -400C (3.5) showed

three signals for the C-2 carbon. Using the rule that the

carbon syn to the carbonyl was the most shielded, the most

downfield signal was assigned to (3.5c), the most upfield

signal to (3.5a) and the remaining one to (3.5b). Based on

similar considerations, of the two signals seen for the C-2

carbon of (3.6), the most intense was assigned to (3.6b).

Since the remaining one was at a higher field than (3.6b),

it was assigned to (3.6a). These assignments agree with

conformer populations deduced from the proton spectra.

Assignments for the C-4-C-6 carbons were made similarly.
















.)-
O
00 c -4 0 C


r- r- r-I r- u


m



W


u u
m m AN


U m m n


m U U-
) A n L n m


u u
C m0 U .
( S 0M C
I U m l N
-- U
S0O U
) LA ( J




UP U U

-N -m 0


U m m m
<-l4 -


U
0 0
>1


* LA


















0 r_
5s; un
U
a)
C




(D
--I
4-,

>4

(N
U





0 C


6 0 4-i
0 U to
U 6





E U
a o

E*4


U U
0 N (N







LO Ln
L'n 1in .n
rM N (N


m m

* C




* *










* rn M






rL 0
(MN a


u
LI
0






u
00





r-1

U 0 U U
co Ln o m n


,-4 ,r-4





m 0 0 0 0






"- Ch -4 fn

1 4 1 -


r4 co '*-. C*















.0 LA LAn Ln






U 'o r1 .0







l) 0
L' 0










r-,-
r l
U < f








in0 o
~d rs) r~


,-I C


r-I -1 r-


u..
0
4-,
C
0
U
t0


C
,-

aU
E



.)-i



-iJ


C
u
















LI
m

4-
i0





















N 0

4)
(NU
E-
Un g

6









3.2.8. 1,31 -Triacylhexahydro-sym-triazines Conformational
Study from C NMR Spectra


The 75 MHz spectra of (3.7) (figure 3.19) and (3.8)

(figure 3.21) at 250C showed signals for the three methylene

carbons at 58.5 and 57.3 ppm, respectively. At -700C for

(3.7) (figure 3.20), signals were seen for the individual

conformers. However, for (3.8) only one conformer (x) was

observed even at a temperature as low as -1100C. This was

the same result as seen in its 1H spectrum. The signal

assignments for the two conformers (x) and (y) of compound

(3.7) and one conformer (x) of compound (3.8) were also

based on the model compounds discussed earlier. The signal

assignments are shown in Table 3.6.



3.2.9. Kinetic Parameters


The kinetic parameters obtained were the free energy

difference between conformers and the free energy of

activation for the barrier to rotation around the amide

C(O)-N bonds. The free energy differences (AG) were

calculated from the population ratios (of their C-2

methylene protons signals) obtained for each of the amides

from their 1H NMR spectra and are given in table 3.7. Free

energies (AG), which are compensated for the entropy factor

(for the topomers of unsymmetrical isomers), are also given

in table 3.7.










































0



'0

co Z U


\0


C
--I




*E-
N



In





0



c1





0
CN

.0
.4





4,








E-



U





U
a









-I
U
U







N-





rin




















tcl


a,

Lr)
N

-I
4J


I

0
>9
m

an


-4

o

N

.0




LA

m









.J)
a,





E
1-1
1













U
L

U


Zm










*0








0
CN


O N




I-I




>1



'-I




.
C '-4


V--4
m 0







o o u


1 O -- O
j 1-1















uca
00
) *




CO






oto -I

24
0
(rT- e-1

















TU
o U 0







U-.
- \W



0 (N



u-






















Ln o r a- i WO Ln

-0 0 4-t 0 T '- LA


U U U U
o y m o r>


U m m m r m r
T-l -1 1 1 1- 1-


4) M

C U

4 u


Z 0


un U
0U




E-4









, C o
0







I CM
a 0o N






U
















0 o
a)
4.I
0
0.. '4 -


LA r- Ln m R


(M (M (N (N (N



U U U U
LA 01 co C< 'o o


(N N (N N N N (N
-4 -4 -4 -4 -4
u u u u
(N (n o 'IT r- -o





m m (N (N r1 N










M m M m im
-4 -4 -4 -4 -4

















r- X >1 co x









LA 0 La 0
(N r- (N
I IL
Lr) CD Y) C


0O

0







0

0
U
0





u
a)
E
C


-4
U)
U)

ca






C-
a)

























>
u








N U
a)




EO









u a)
0

41
a a

N aU

O
0
NU

a) C























0o o


0 (N

C


m a
* 0 0 .
0 0


0
CN
0 0
-- 0









0



o


S0 0
r-4 -


a)


.,4 -4
10

(U U 4 .,o
C 0 Ul
Sl


W nCD C

0 0


1 *H 4 -) C -






O r 0







S0 0
4J 4-> '~ -
00 4-








:1 C ro



,,-- I -



S. o
M 0H
C.4-4 *-I










(O )
O-4




1 a10 ) 0




W 44
SO,3
(0 *- 0 -
4J U U3 '-













) 04-






0- (13 = o

>0 3 0 Z
-4 T )- a4


) 0 >C

O U3 i-i U3
4 a m






w 0 'r 0





S0
u) o4 a)






a > t O-i




.1 4-4
Q g a e- a)






U) >* 0 0
( 4.1 ri U (r








a) .0 O C
ru4 "T -l ~


1-4
0


1-

u



0

I


a(m





a m









In imidazolidines (3.3) and (3.4), (b) was the most

stable conformer both before and after compensating for

entropy. However, the relative stability of conformers (a)

and (c) became interchanged on going from (3.3) to (3.4).

In hexahydropyrimidines (3.5) and (3.6) (b) was the

most stable conformer. However, after the correction for

entropy in (3.5), (a) becomes the most stable conformer. In

(3.6), conformer (c) is not observed at all.

In hexahydro-sym-triazine (3.7) (y) was the most stable

conformer, but after compensating for entropy, (x) became

the most stable conformer. In (3.8) conformer (y) was not

observed at all.

In conclusion, the conformer in which the two tert-

butyl groups were on the same side became either the least

stable conformer or was not observed at all.

The free energy of activation (6G ), for the barrier to

rotation around the amide C(O)-N bonds, was calculated from

the coalescence temperature observed in the 1H NMR spectra,

for the methylene protons (N-CH2-N) (table 3.8). All the

amides showed only one coalescence temperature, except for

compound (3.8) which showed only one conformer even at very

low temperature (-1100C).











Table 3.8 Coalescence Temperatures and Free Energies of
Activation of Amides (3.3 3.8).


A v
(observed
exchange
in N-CH2-N)


Amide






(3.3)



(3.4)



(3.5)



(3.6)c


Coalescencea
temperature
(Tc)


66
84


33
45


48
111


12
-


(x)-(y) 36
99


A G
(kcal mole-1
Rotational
Barrier


303


248


298


14.7
14.6


12.3
12.2


14.7
14.2


9.0



13.0
12.5


177


263


(3.8)d


a Only one coalescence temperature was observed.

b Calculated using the equation

A G /RTc = 22.96 + log (T /A v)

c Only two conformers (a) and (b) were observed.

d Only one conformer (x) was observed.


(a)-(b)
(b)-(c)


(a)-(b)
(b)-(c)


(a)-(b)
(b)-(c)


(a)-(b)
(b)-(c)


(3.7)









Since imidazolidines and hexahydropyrimidines have

three conformers, two Av values were obtained (one between

conformers (a) and (b) and the other between (b) and (c))

and hence two free energies of activation were obtained for

each of the amides. Both values differed by + 0.5 kcal

mole .

For hexahydro-sym-triazine (3.7) four signals were seen

for the two conformers. The three equal intensity signals

at 5.26, 5.37 and 5.71 ppm were assigned to conformer (y)

and the remaining signal at 5.38 ppm was assigned to

conformer (x) (see Table 3.3). The signal at 5.37 and 5.38

ppm were almost the same, hence for the conversion of (x) to

(y) two Av values were obtained (one between 5.26 and 5.38

ppm and the other between 5.71 and 5.38 ppm). The two

calculated free energies of activation differed by + 0.5

kcal mole-1

The benzamides had higher fr-ee energies of activation

than the corresponding pivalamides. The free energy of

activation for 1,3,5-tribenzoylhexahydro-sym-triazine (3.7)

was lower (by 2 kcal mole-1) than that for the benzoyl

derivatives of imidazolidine (3.3) and hexahydropyrimidine

(3.5). This decrease in activation barrier might possibly

be due to less energetic rotation processes (discussed in

section 3.2.10).









3.2.10. Mechanism of Conformer Interconversion



Amides interconvert by bond rotation, and the

interconversion pathway is unambiguous for monoamides with

only two conformers. However, there has been no mention in

the literature about the two possible directions of rotation

for the conformer interconversion, clockwise or

anticlockwise. This possibility becomes relevant when a

chiral center is present, either at the a position to the

nitrogen or carbonyl group, or when more than one amide

group is present, such as peptides where the sequence

(individual or concerted) of rotation about the different

amide C(O)-N bonds also becomes an important factor.

Compounds like N-acyl-2-substituted saturated

heterocyclic amines [72CC788, 78JCS(P2)1157, 67CB3397,

75BCSJ553, 77BP1465, 83CJC2572] and 1,3,5-trinitroso-sym-

triazine [78JMR131] have been investigated by DNMR.

However, there has been no mention of the clockwise or

anticlockwise rotation of the amide C(O)-N and the nitroso

N-N bonds, respectively.

From band shape analysis of the exchange broadened

spectra of 1,4-dinitrosopiperazine, cis-2,6-dimethyl-1,4-

dinitrosopiperazine, trans-2,5-dimethyl-l,4-

dinitrosopiperazine and 1,3,5-trinitrosohexahydro-sym-

triazine, the possibility of correlated two bond rotations









has been excluded, and the spectra have been found to be

consistent with the exclusive operation of sequential

processes [78JMR131].

Correlated rotations have been found to be the

favorable process in triphenylmethyl cations [68JAM4679], in

certain substituted [2.2.2.2]paracyclophanetetraenes

[84TL4787] and in triarylboranes, methanes and amines

[76ACR26].

In triaryl cations, the most favorable mechanism for

interconversion of propeller conformers has been proposed to

be the three ring flip [68JAM4679]. In triaryl boranes,

methanes and amines, of all the possible rotations the

favorable and the lowest energy rotation has been found

theoretically to be the two ring flip, in which two rings

rotate in one direction while the third rotates in the

opposite direction [76ACR26].

For the amides (3.3-3.8) with more than two conformers

the rotations around the amide C(O)-N bonds could either be;

(A) individual (sequential), or (B) concerted (correlated)

[78JMR131].

Compounds (3.3), (3.4), (3.5) and (3.6) can exist in

three distinct conformers (a), (b) and (c) (scheme 3.2 and

3.3). For each of these amides, mechanism (A) (going along

the sides of the square) interconverts conformers (a) and








R R R 0-

0 (a) 0 0 ,(b) R


Scheme 3.2


0 R 0


R (b) 0 R


(3-3)R= CH5
(3.4) R= C(CH3)


Scheme 3.3


(c) R


(b) 0


(3-5) R=C6H5
(3-6) R=C(CH3)3









(b), and conformers (b) and (c), but not directly (a) to

(c). On the contrary, mechanism (B) (going along the

diagonal of the square) directly interconverts (a) and (c),

whereas (b) interconverts only with its topomer

[71AG(E)570].

For the tris-amides (3.7) and (3.8) (scheme 3.4),

mechanism (A) (going along the sides of the cube)

interconverts conformers (x) and (y), as well as changing

conformer (y) into its topomers. Mechanism (B) has two

possibilities. Firstly, when two amide bonds rotate and the

third does not (going along the diagonal of the faces of the

cube). This interconverts conformers (x) and (y) as well as

changing conformer (y) into its topomers. Secondly, when

all three amide bonds rotate (going along the diagonal of

the cube). In this case both (x) and (y) merely change into

their corresponding topomers [71AG(E)570] (scheme 3.4).

At higher temperatures, fast rotation around the amide

C-N bonds should lead to a singlet in the 1H NMR spectrum,

for each methylene between two hetero atoms in the ring,

irregardless of whether mechanism (A) or (B) is operating.

Higher temperature spectra indeed showed singlets for

the C-2 methylene protons of (3.3), (3.4), (3.5) and (3.6).

Similarly, the C-2, C-4 and C-6 methylene protons gave one

singlet for (3.7) and for (3.8).









I
CT ) -
I, II


00





~K
:( o
o --_6_



z o

cr- /

r 'n. zc .o







0 O




0-0

oz



Z 0 cr

SO 0
,. 00o
< r--------"


0=0 \ Q \









As the temperature was lowered, these CH2 signals for

(3.3-3.7) broadened, coalesced and separated as expected

into two or more peaks. Surprisingly, the signal for

compound (3.8) remained as a singlet even at -1100C.

Thus it can be assumed that in compound (3.8) the

rotations around the amide C(O)-N bonds could be correlated,

that is, all three amide bonds rotate simultaneously.

However, the possibility of three sequential rotations with

conformer (y) as a short lived intermediate in the

transitory state can not be ruled out. The two ring flip

mechanism [76ACR26] as seen in R3Z compounds, where Z

represents either B, CH or N, and R represents aryl groups,

can be extended to compound (3.8) where R represents the

pivaloyl group and Z represents the hexahydro-sym-triazine

group.

Since DNMR spectroscopy deals exclusively with the

phenomenon of site exchange among nuclei, and is

uninformative with respect to intermediate states, the

information about transitory states can not be obtained.

However, for the present system it can be extrapolated from,

results that have been obtained on triaryl boranes using

molecular mechanics [76ACR26], and simple 1,3-type

interactions [68CJC2821].









Considering only simultaneous (correlated) rotations

for compounds (3.3), (3.4),(3.5) and (3.6), the rotations

around the amide C(O)-N bonds could be either in the same

direction or in opposite directions. For conformers (a) and

(c) if the rotation is in the same direction then in the

transition state the R groups point in the opposite

direction. However, if the rotation is in opposite

directions then in the transitory state the R groups point

in the same direction. Thus from simple 1,3-type

interactions [68CJC2821] same side rotations would be

favored. For conformer (b) the converse is true, that is

opposite side rotations are favored.

On extending similar arguments for the different

conformers of compound (3.7) and (3.8), it is obvious that

there are three possible ways for the simultaneous

rotations: (i) one amide bond in one direction and the other

two in the opposite direction, (ii) two amide bonds in one

direction and the third in the opposite direction and (iii)

all the three amide bonds in one direction, of which (i) and

(ii) are essentially the same.

Conformer (x) which is similar to conformer (b) can not

rotate in the same direction since all the R groups will

point in the same direction in the transitory state which is

not a favorable process. Hence it has to go through either









(i) or (ii) which are the same. For conformer (y) however,

either of the mechanisms (i) (or (ii)) or (iii) would

produce the same transitory state. So conformer (y) can

rotate by either of the two possible mechanisms.



3.3. Conclusions



Low temperature 1H and 13C NMR spectra were reported

for 1,3-diacylimidazolidines, 1,3-

diacylhexahydropyrimidines, and 1,3,5-triacylhexahydro-sym-

triazines. Peaks for the individual conformers found were

assigned by using model compounds, from relative

intensities, and by internal consistencies.

Conformer populations, the energy difference and the

energy barrier for their interconversion between them were

deduced (Table 3.7 and Table 3.8). A mechanism for their

interconversion was proposed.

Conformer populations and the energy difference between

the conformers indicate that the conformer in which the two

tert-butyl groups point towards each other is the least

populated and hence the least stable. This was most

pronounced in compounds (3.6) and (3.8) where such a

conformer was not observed at all.