Effects of heteroatoms in heterocyclic molecules
by Kauo-rong Sun
A thesis submitted to the Graduate Faculty in partial fulfillment of the requirements for the degree of
MASTER OF SCIENCE in Chemistry
Montana State University
© Copyright by Kauo-rong Sun (1972)
Abstract:
By utilizing data obtained from chemical and spectroscopic studies, the ground state conformation of
an oxygen-containing heterocyclic compound, cis-8-oxabicyclo [4.3. 0]non-3-ene, has been
established. A long-range electronic participation from the π-system of the double bond to the
nonbonded electrons of the oxygen was proposed from the spectroscopic study.
Cis-7,7,9,9-tetramethyl-8-oxabicyclo [4.3.0]non-3-ene was prepared, and the conformation of this
molecule was proposed by utilizing chemical and spectroscopic data. Furthermore, the spectroscopic
study indicated the blockage of the electronic participation between the 77-system of the alkene and the
nonbonded electrons of the oxygen atom due to the steric factor of the four methyl groups.
A similar spectroscopic study was extended to the nitrogen analogs, the cis-N-substituted-8-azabicyclo
[4. 3. 0]non-3-ene systems. The primary data led to the proposal of the nitrogen inversion and the
similar electronic participation was obtained. STATEM ENT
OF
PER M ISSIO N T O
CO PY
In presenting this th esis in partial fulfillm ent of the requirem ents for an
advanced degree at Montana State U niversity, I agree that the Library shall
make it freely available for inspection.
I further agree that perm ission for
extensive copying of th is th esis for scholarly purposes may be granted by my
major p ro fesso r, or, in his absence, by the D irector of L ibraries.
It is under­
stood that any copying or publication of this th esis for financial gain shall not
be allowed without my written perm ission.
Signature
Date
cco - ’JZd>z£.
u
EFFECTS OF HETEROATOMS IN HETEROCYCLIC MOLECULES
by
KAUO - RONG SUN
A th esis submitted to the Graduate Faculty in partial
fulfillm ent of the requirem ents for the degree
of
MASTER OF SCIENCE
in
Chemistry
Approved:
Head, Major Department
Gr^d^ate Dean
I
MONTANA STATE UNIVERSITY
Bozeman, Montana
August, 1972
To
My Parents, Wife, and Daughter
iv
ACKNOWLEDGEMENT
I would like to take th is opportunity to exp ress my gratitude to the many
people and faculty m em bers who helped make this th esis p o ssib le.
In particular,
I would like to thank my w ife, Chyun-mei, and my resea rch advisor, Dr. Brad­
ford P . Mundy, who made the hard days e a sie r to pass with! th eir encouragement
and understanding; and also my parents who gave me the ability and the d esire
to com plete th is resea rch study.
A lso, I would like to thank P ro fesso rs Richard Geer and Arnold Craig
for th eir helpful d iscu ssion s and for allowing me to use som e of their books.
A sp ecial thank you goes to Gail P eterson and Phyllis W alters for typing the
rough draft of th is th esis.
Acknowledgement is also due to the chem istry department for its
financial support in the form of teaching assistan tsh ips.
A portion of this
resea rch has been supported by a grant from the Petroleum R esearch Fund,
adm inistered by the A m erican Chemical Society.
/
V
TABLE OF CONTENTS
Page
VITA
ii
ACKNOWLEDGEMENT
iv
LIST OF TABLES
vii
LIST OF FIGURES
ix
ABSTRACT
xii
PART I.
The Conformation of C is-8-oxab icyclo [4.3. 0]
non-3-ene
1.1
Introduction
I
1 .2
Synthesis
6
1 .3
nmr Spectroscopic Data
9
1 .4
Hydroboration
1.5
PART II.
C is-8-oxab icyclo [4„ 3i 0] nonan-3-one
16
19
Synthesis and Reactivity of C is - 7 ,7, 9, 9 -tetr a m eth yl-8-oxab icyclo [4 .3 . 0]non-3-ene
IL I
Introduction
23
H. 2
M olecular Model
23
II. 3
Synthesis
24
II. 4
nmr Spectroscopic Data
26
II. 5
Oxymercuration
27
H. 6
nmr Study for the E lectronic Participation
30
PART III.
C is-N -su b stitu ted -8-azab icyclo [4. 3. 0] non-3-ene
System s
HI. I
Introduction
36
III. 2
Synthesis
37
HI. 3
nmr
38
study for the E lectronic Participation
vi
TABLE OF CONTENTS (CONTINUED)
in. 4
R elation to the Corresponding Oxygen System s
50
EXPERIMENTAL
General Information
51
Part I
51
Part H
59
Part III
64
APPENDIX
I.
The A nalysis of Gas Liquid Chromatography
67
II.
The Commonly Used Gas Liquid Chromatography
Columns
68
The Commonly Used Nam es of Some of the
H eterocyclic Compounds
69
The nmr Spectra of Some of the H eterocyclic
Compounds
70
III.
IV.
REFERENCES
89
vii
LIST OF TABLES
Table
page
I.
Competition R esults of Oxymercuration Reaction
2.
Tentative Coupling Constants From Conformations
of C is- 8 -oxabicyclo [4. 3. 0]non-3-ene
15
R esults From Reduction of C is-8-oxabicyclo [4 .3 . 0]
nonan-3-one
19
Report of Elem ental A nalysis of 3 , 5-dinitrobenzoate
D erivative of C is -7 ,7 ,9 , 9-tetram ethyl-8-oxabicyclo
[ 4 .3 .0 ] nonan-3-ol
30
The Observed Chemical Shifts of Protons in C is -8 oxabicyclo [4. 3. 0]non-3-ene From nmr Studies
32
The Observed Chemical Shifts of Hydrogens in
C is-7 , 7 ,9 , 9-tetram ethy 1-8-oxabicyclo [4 .3 . 0] non3-ene From nmr Studies
32
The Observed Chemical Shifts of Hydrogens in
C is-8-oxab icyclo [4.3. 0 ]nonane From nmr Studies
34
The Observed Chemical Shifts of Hydrogens in
C is - 7 ,7, 9, 9-tetram ethyl-8-oxabicyclo [4 .3 . 0] non3-ene at Different Concentrations in Acidic Solvent
35
The Observed Chemical Shifts of Hydrogens in
C is-8-p h en yl-8-azab icyclo [4 .3 . 0]non-3-ene From
nmr Studies
39
The Observed Chemical Shifts of Hydrogens in
C is-8-p h en yl-8-azab icyclo [4 .3 . 0] nonane From
nmr Studies
40
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
The Comparison of Observed Chemical Shifts of
. Hydrogens in C is-8-p h en yl-8-azab icyclo [4. 3. 0] non3-ene and its Quaternary Methiodide Salt
The Comparison of Observed Chemical Shifts of
Hydrogens in C is- 8 -phenyl-8-azab icyclo [4. 3 .0 ]
nonane and its Quaternary Methiodide Salt
2
41
41
viii
LIST OF TABLES (CONTINUED)
13.
14.
15.
16.
17.
18.
19.
20.
The Observed Chem ical Shifts of Hydrogen in
C is-8-p rop yl-8-azab icyclo [4. 3. 0]non-3-ene From
'nmr Studies
42
The Comparison of Observed Chemical Shifts of
Hydrogens in C is- 8 -propyl-8-azabicyclo [4‘. 3. 0 ] non-'
3-en e and its Quaternary Methiodide Salt
43
The Observed Chemidal Shifts of Hydrogens in
C i s - 7 ,7 ,9, 9-tetradeutero-8-propyl-8-azab icyclo
[4.3. 0] non-3-ene From nmr Studies
47
The Comparison of Observed Chemical Shifts of
Hydrogens in C is -7 ,7 , 9, 9-tetrad eu tero-8-p rop yl-8azabicyclo [4 .3 . 0]non-3-ene arid its Quaternary
Methiodide Salt
48
The Observed Chemical Shifts of Hydrogens in
C is-8-p h en yl-8-azab icyclo [4 .3 . 0] non-3-ene in
Solvents of Different A cidities
49
The R elative Retention Time of Compounds From
C is-8-oxab icyclo [4 .3 . 0]non-3-ene System From
Analytical Gas Chromatography
56
The Observed Yield of Reactions From C is-8 -o x a bicyclo [4. 3. 0]non-3-ene System When Analyzed by
Gas Chromatography
56
The R elative Retention Time of. Compounds From
C is -7 ,7 , 9, 9-tetram ethyl-8-oxabicyclo [4.3. 0] non3 -en e System From Analytical Gas Chromatography
63
ix
LIST OF FIGURES
Figure
I.
The C is-8 -h etero -b icy clo [4.3. 0] non-3-ene System s
I
2.
The Long-range Oxygen Participation
3
3.
The Products From Oxymercuration-dem ercuration
Reaction of Ci s - 8 -oxabicycIo [4. 3. 0]non-3-ene
3
Suggested P o ssib le Conformations of C is-8-oxabicyclo
[ 4 . 3 . 0]non-3-ene
4
Suggested P ossib le Conformations of C is-bicyclo [4 .3 . 0]
non-3-ene and C is-bicyclp [4. 2. 0 ]o ct-3 -en e
4
6.
Preparation of C is-8-oxabicyclo [4. 3. 0]non-3-ene
6
7.
The M ain- and By-product of Lithium Aluminum Hydride
Reduction of C is - 1 ,2 ,3 , 6-tetrahydrophthalic Anhydride •
6
8.
M echanism of Cyclization to the B icy clic System
7
9.
Preparation of C is-7 , 7-dideutero-8-oxabicyclo [4 .3 . 0]
non-3-ene
7
The Protons Adjacent to the Ether Oxygen in C is-8 -o x a bicyclo [4 .3 . 0] non-3-ene and C is-7 ,7 -d id e u ter o -8 -o x a bicyclo [4 .3 . 0] non-3-ene
9
P ossible Conformations of C is-8-oxabicyclo [4 .3 . 0]non3-ene
10
The Observed Dihedral Angles in Models of Conforma­
tion 2-1
11
Partial nmr Spectrum of Hydrogens Adjacent to the Ether
Oxygen of C is-8-oxabicyclo [4 .3 . 0]non-3-ene
12
The Angular Dependence of the Geminal and Vicinal
Proton-proton Coupling Constants
13
The Observed Dihedral Angles in Conformation 2-II and
2 -IH, From Space-filling M olecular Models
14
P ossib le Conformations of Thujopsene
16
4.
5.
10.
11.
12 o
13.
14.
15.
16.
X
LIST OF FIGURES (CONTINUED)
17.
The T ransition States of Hydroboration of C is-8 -o x a bicyclo [ 4 .3 .0 ] non-3 -e ne
17
The Products From Hydroboration of C is-8-oxabicyclo
[4 .3 . 0] non-3-ene
18
19.
Steric Approach Control v s. Product Development Control
20
20.
T orsional Strain y s . Steric Strain
21
21.
P o ssib le Conformations of 23_, and the P ossible Approach
of the Metal Hydrides to the Carbonyl Function
22
P ossib le Conformations of C is - 7 ,7 ,9 , 9-tetram ethyl- 8 oxabicyclo [4. 3. 0]non-3-ene
23
Preparation of C is - 7 ,7 ,9 , 9-tetram ethyl-8-oxabicyclo
[ 4 .3 . 0] non-3-ene
24
The Grignard Reaction of D im eth y l-cis-4 -cy clo h ex en e1 , 2-dicarboxylate
25
C is- and T rans- 7 ,7 , 9, 9-tetram ethyl-8-oxabicyclo
[ 4 .3 . 0] non-3-ene
26
P ossib le Product or Product Mixture From Hydration
of Conformation 3-H and 3 -III
28
The Observation of the Product Mixture From the Oxym ercuration of C is - 7 ,7 , 9 , 9-tetram ethyl-8-oxabicyclo
[ 4 .3 .0 ] non-3-ene by an Analytical Gas Chromatography
29
The Long-range E lectronic Participation Between the
77-system of the Double Bond and the Nonbonded E lectrons
of the Oxygen Atom in C is- 8 -oxabicyclo [4.3. 0 ]non-3-ene
31
29.
C is-8-oxab icyclo [ 4 .3 .0]nonane
33
30.
The C is-N -su b stitu ted -8-azab icyclo [ 4 .3 . 0]non-3-ene
System s
36
Preparation of C is-N -substituted-8-azab icyclo [4 .3 . 0]
non-3-ene System s
37
18.
22.
23.
24.
25.
26.
27.
28.
31.
Xl
LIST OF FIGURES (CONTINUED)
32.
Preparation of the Quaternary Methiodide Salt of the
C is-N -su b stitu ted -8-azab icyclo [4. 3. 0 ] non-3-ene
System s
37
C is-8-p h en yl-8-azab icyclo [4. 3. 0] nonane and its
Quaternary Methiodide Salt
38
P o ssib le Conformations of Nitrogen Inversion of
C is-8-p rop yl-8-azab icy clo [4 .3 . 0] non-3-ene
44
35.
The Quinolizidine Ring System
44
36.
The A ziridine System
45
37.
The N -substituted-2, 2-dim ethyl A ziridine System s
38. ,
The C is-7 -ch lo ro -7 -a za b icy clo [ 4 .3 .0 ] heptane System
46
39.
Stereosp ecific Synthesis of C is-8-oxab icyclo [4 .3 . 0]
nonan-3 -ol-en do
54
The Observation of Compounds in Table 18 From an
Analytical Gas Chromatography
56
The Observation of the Product Mixture From Dehydra­
tion of C is -o s a , Oy9a ’, -tetram ethyl- 4 -c y c lo h e x en e-1 ,2 -d i­
methanol From an Analytical Gas Chromatography
60
The Observation of Compounds in Table 20 From an
Analytical Gas Chromatography
63
33.
34.
40.
41.
42.
* 45
xli
ABSTRACT
By utilizing data obtained from chem ical and spectroscopic studies, the
ground state conformation of an oxygen-containing heterocyclic compound,
cis-8 -o x a b icy clo [4.3. 0]n on-3-ene, has been established. A long-range e le c ­
tronic participation from the 77-system of the double bond to the nonbonded
electrons of the oxygen was proposed from the spectroscopic study.
C is - 7 ,7, 9 ,9 -te tr am ethyl-8-oxabicyclo [4.3. 0]non-3-ene was prepared,
and the conformation of this m olecule was proposed by utilizing chem ical and
spectroscopic data. Furtherm ore, the spectroscopic study indicated the block­
age of the electronic participation between the 77-system of the alkene and the
nonbonded electrons of the oxygen atom due to the steric factor of the four
methyl groups.
A sim ilar spectroscopic study was extended to the nitrogen analogs, the
cis-N -su b stitu ted -8-azab icyclo [4 .3 . 0]non-3-ene sy stem s. The primary data
led to the proposal of the nitrogen inversion and the sim ila r electronic p artici­
pation was obtained.
P A R 'I' I
THE CONFORMATION OF CIS-8-OXABICYCLO [4. 3. 0]NON-3-ENE
INTRODUCTION
Compounds containing a ring made up of more than one kind of atom are
called heterocyclic compounds, and are often found in drugs, natural products,
and many biologically important m olecules.
The role of the heteroatoms in the
m olecule is important, and is different from that of a carbon atom.
Yet, the
influence of the heteroatom to the conformation, stereoch em istry, and rea c­
tivity of the whole m olecule is still unknown in many heterocyclic system s.
In this laboratory, som e sim ple heterocyclic sy stem s, as shown in
figure I, have been studied.
The main interest of the investigation concerns
the influence between the heteroatom s and the alkene bond.
CO 2
PR
Z =O 1N-R1
R =H 1D1CHi
I
CCN~R
’^
Figure I: The Structure of C is-8 -h etero -b icy clo [4. 3. Ol non3-ene System s.
C is-8 -o x a -b icy clo [4. 3. 0]n on-3-ene, (2), has been used as a model for
the corresponding carbocyclic compound1. It has been assum ed that this oxygencontaining heterocycle w ill exhibit steric and conformational characteristics
sim ilar to the corresponding carbocycle, esp ecially in reactions on the cyclo­
—2 —
hexene m oiety.
However, in recent investigations of other oxygen-containing
h eterocycles, the influence of the heteroatom on the reactivity of the whole
m olecule has been noted.
These changes in reactivity, relative to the c o r r e s2
ponding carbocyclic sy ste m s, can be rationalized by resonance , inductive
e ffe c ts3 , dipole e ffects4 , directive and electron ic effects5 , 6 , and conform a7
tional effects due to the presence of the heteroatom s.
8 9
From this laboratory, Mundy and Otzenberger * reported the compe­
tition resu lts of oxym ercuration-dem ercuration reaction, (shown in Table I)
and proposed the contribution of the oxygen in 2^to the chem istry of the alkene
bond5.
Table I: Competition R esults of Oxymercuration
Compound
Compound
No.
Relative
Rate
-3 -
The eightfold increase of reactivity of 2_ as compared to 6 demonstrated that
the alkene bond in 2 was more reactive.
They suggested that the non-bonded
electron s of the oxygen stabilized any incipient charge which might result from
electrophilic attack on the TT-system of the alkene.
This interaction, as indicated
by £, might be sim ilar to the long-range oxygen participation reported by
3
Paquette for IlO .
9
IO
Figure 2: The Long-range Oxygen Participation
The products of the oxymercuration from cis-8 -o x a b icy clo [4 .3 . 0] non3-en e, (2), w ere cis-8 -o x a b icy clo [4. 3. 0] nonan-3-ol-endo, (11), and c is -8 -o x a bicyclo [4. 3 .0 ] nonan-3-ol-exo, (12), as shown in Figure 3.
I. Hg(OAc)2
0
2. NoBHa
^ HO
2
12
Ratio*
3
:
I
(♦Reaction repeated by this worker)
Figure 3: Oxym ercuration-Dem ercuration Products From C is-8 oxabicyclo [4. 3. 0]n on-3-ene.
-4 -
Otzenberger
also proposed that the ground-state conformation of 2,
among all the possible conform ations, was 2-H (figure 4).
2-1 was the distorted
pseudo-chair conformation; 2 -II and 2-III w ere the two possible boat conforma­
tions.
Figure 4: P ossible Conformations of C is-8-oxabicyclo [4 .3 . Ol non3-en e.
C asadevall10 proposed that the ground state conformation of c is-b icy clo
[ 4 .3 . OI non-3-ene, (6), was 6-HI (figure 5), based on the result of epoxidation
reaction.
Figure 5: Suggested Conformations of C is-bicyclo [ 4 .3 . 0] non-3-ene
and C is-bicyclo [4. 2. 0] oct-3 -en e.
The rationalization was that if 6-II were the preferred conformation, epoxidation
should have yielded approximately a 50:50 mixture of the endo and exo epoxides.
But if 6-III w ere preferred, one expected to find that the top side of the m olecule
was m ore hindered than the bottom side (figure 5), therefore, the exo-epoxide
-5 -
should have predominated.
The resu lts w ere that the endo.exo ratio was 14:86
which indicated that the 6-III was preferred.
Cope11 also reported sim ilar ratio (13:87) for the endo:exo epoxides
from epoxidation of c is-b ic y clo [4 .2 . 0lo o t- 3 - e tie, (13), and proposed that the
conformation was 13-HI, based on the sam e argument.
Cope11 and C asadevall10
concluded that the cis-fu sed cyclohexene compounds 13^ and 6 existed respectively
in the pseudo-boat form .
9
Otzenberger suggested that 2-I_ was not the conformation.
However,
because of lim iting data, there was little concrete support for this suggestion.
This need for supporting data led this research er to the investigation of the
12
fir st part of this report .
SY N TH ESIS
C is-8-oxab icyclo [4. 3. 0] non-3-ene, (2), was prepared according to
figure 6.
Figure 6: Preparation of C is-8-oxab icyclo [4 .3 . 0] non-3-ene.
The com m ercially available anhydride 14 was reduced to the c is-d io l 15
by lithium aluminum hydride.
The interesting by-product obtained from this
reaction was the lactone (16) (figure 7), as evidenced by infrared spectroscopy.
14
15
IG
Figure 7: The Main and By-products of LiAlH4~reduction of C is-1 ,
2 ,3 , 6-tetrahydrophthalic Anhydride.
It was noted that further reduction of the lactone (16) with lithium aluminum
hydride gave a quantitative yield of the diol (15).
The diol was then converted to the tetrahydrofuranyl sy stem , presumably
by way of a m onotosylate under conditions for which it was known that system s
of this type readily underwent cyclization to the bicyclic sy stem s (figure 8).
The
-7 -
product 2 was identified by infrared spectroscopy and mnr.
x X Z ^ s CH2OTs
o 2
Figure 8: Mechanism of Cyclization to the B icyclic System s
For the investigation of nmr spectroscopic data to confirm that the con­
formation 2-1 was not the ground-state conform er, it was necessary to prepare
13
c is-8 -o x a -b icy c lo [4. 3. 0 ] - 7 , 7-dideutero-non-3-ene , (19), (figure 9).
CD2OH
CH2OH
Figure 9: Preparation of C is-8-oxab icyclo [4.3. 0] - 7 , 7 -dideuteronon-3-ene.
-8 Following the method of B ailey14, the anhydride (14) was first reduced
to the lactone (16) by sodium borohydride, then further reduced to the 1 , 6-diol
(18) by lithium aluminum deuteride, and then cyclized to 19 by p-toluensulfonyl
chloride in pyridine.
The bicyclie compound (19) was verified by infrared
spectroscopy, and used for nmr investigation.
NM R S P E C T R O S C O P IC DATA
The nmr spectrum of 2 exhibited a multiplet for the protons adjacent to
the ether oxygen, and the spectrum of 19 exhibited the sam e m ultiplet, but with
only half the "intensity".
(The full nmr spectrum of 2 is attached in Appendix IV;
the partial nmr spectrum of the protons adjacent to the ether oxygen of 2 is shown
in figure 13).
This required that Ha and Ha t share equivalent magnetic environ­
m ents, as must Hy and Hyt (figure 10).
Figure 10: The Protons Adjacent to the Ether Oxygen in Compounds
2 and 19.
By examining sp ace-fillin g m olecular m odels of 2, one could observe
three different conformations - 2-1, 2 -II, and 2-HI (figure 11); and in each con­
formation, there w ere three p o ssib ilities, A, JB2 and_C.
In B, the tetrahydro-
furan m oiety was flat.
One could observe that Hy and Hy, w ere in entirely different environ­
m ents in conformation 2-1; the Hyt was c lo se to the 77-system of the double bond,
while Hy was far away from the double bond.
One also would observe further
information supporting that Hy and Hy, w ere in different environments from the
dihedral angles.
Since the tetrahydrofuran moiety was distorted in conformation
2-1, it was im possible to keep this fiv e -m em bered ring flat.
conform ers 2 -I-A and 2-I-C w ere d iscussed here.
Therefore, only
The dihedral angle between
the H c-C so-C q, and CgO-Ca -Hy planes was 150t 10°, and that between the
—10 —
Figure 11: P ossible Conformations of 2.
Hc -C 3O-C^and C go-C ^-H y planes was 120t 10° in 2 -I-A . In 2 -I-C , the c o r r e ­
sponding dihedral angles w ere 1651 10° and 1351 10°, respectively (figure 12).
All this information clearly indicated that the ground state conformation was not
2 - 1.
In both conformation 2-II and 2 -III, one would observe that Ha and Ha ',
and Hy and Hy, w ere in the sam e environments resp ectively.
For the three nonequivalent protons Ha (Ha ,), Hy (H y), Hc (Hc '), an
ABX system was designated by following S ilverstein15 and Pople16. From the
analysis of the nmr spectrum of 2 (figure 13), Ha (Ha,) differed in chem ical
shift from Hy (Hy,) by 22. 2 cy cles per second (cps).
Ha (Ha ,) coupled with
-11
,C
0
2 -I-A
C
O
IBOiIO0
ieo±ioe X -^
C
2-I-C
I65±I0°
Co
0
I35d
Figure 12: The Observed Dihedral Angles in Models of Conforma­
tion 2-1.
Hy (Hyl) resp ectively with a coupling constant, Jay (Ja 'b')> ° f 7. 8 cps.
(The
only other coupling available now was between Ha and Hc , and Hy and Hc ).
The
interpretative problem was faced because coupling constant - dihedral angle
relationships have not been w ell studied for heterocyclic sy stem s.
However the
reported dihedral angle-coupling constant relationships for carbon system s
would be used tentatively.
( Karplus1
7
^ has pointed out the dependence of coupling constant, J,
on bond angles for both the coupling between the geminal protons and the coupling
between protons on vicinal carbons in carbon system s) (figure 14).
The conformation 2-III-A clearly indicated the repulsion between the
nonbonded electron s of the oxygen atom and the rr-system of the double bond,
by their close proxim ity.
The dihedral angle between Hc -C 3O-C0, and C30-C Qf-Hy planes and also
that between Hc -C g o -C 0, and C go-C a -Ha planes in conformations 2-II, 2 -III-B ,
-1 2 -
Figure 13: Partial NMR Spectrum of Hydrogens Adjacent to the
Ether-oxygen of C is-8-oxab icyclo [4.3. 0]n on -3-ene.
-1 3 -
Figure 14: The Angular Dependence of the Geminal and Vicinal
Proton-Proton Coupling C on stan ts^ .
and 2-III-C w ere carefully investigated and shown in figure 15.
The corresponding tentative coupling constants w ere found by using
17
Karplus
diagram from carbon sy stem s, and were tabulated in table 2. From
th ese approximate figu res, no conclusion could be obtained.
However, if the sim plified observation - trans coupling is usually more
effective than c is coupling - was used, the larger coupling constant 5. 6 cps
would be assigned to the JcJ3, and the sm aller one, 4 .8 cps, to the Jc a . T h ere­
fore, the chem ical shift for Hj3 would be the le s s shielded one, i . e . , 3.836, and
that for Ha would be the 3.466.
conformation.
These indicated that 2-II was the ground state
If 2 -HI w ere the ground state conformation, proton Hj3 would be
expected to be more upfield because it would be influenced by the magnetic
shielding cone of the alkene system .
All in all, as it was already noted, nmr evidence was consistent with,
but did not prove, that 2-II was the ground state conformation.
chem ical evidence to substantiate this assignm ent was required.
Therefore,
-1 4 -
30 ±5
2S ± 5°
Figure 15: The Observed Dihedral Angles in Conformation 2-II,
2-III-B , and 2 -IH -C , From Space-filling Molecular
M odels.
-1 5 Table 2: Tentative Coupling Constants.
Conformation
Jcb
Jca
2-II-A
2 .5
8.2
2-II-B
4 .2
2 -II-C
Larger Coupling
(cis)
7 .4
Jca
tf
7 .0
4 .9
Jcb
(trans)
2 -m -B
4 .2
7 .4
Jca
(cis)
2 -III-C
6.3
5 .3
Jcb
(trans)
I!
HY D ItO B O R A TlO N
The hydroboration-oxidation of olefins has been reported to be a con­
venient procedure for achieving the anti-Markovnikov hydration of carboncarbon double bonds
and to be highly sen sitive to the ste ric environment
20 21
of the double bond and generally takes place from the le s s hindered side ’
This reaction has been also reported to be highly exotherm ic, but is remarkably
18
free of skeletal rearrangem ent . Brown proposed that the transition state for
22
such a reaction should resem ble the reactants . In other w ords, the stereo ­
chem istry of the reaction products can be correlated with the ground state of
23 24
the reactants ’ . Since the reaction of diborane with olefins in ether solvent
22
is very fa st. Brown
strongly suggested that the activation energy for the
hydroboration step may be le s s than that for the interconversion stage of the
flexible cyclic thujopsene (figure 16).
By comparing the possible conformations
of thujopsene and that of the system 2, it is reasonable to suggest that the con­
formational interconversions in the fused ring system 2_ might be also expected
to be higher than the activation energy for diborane addition.
Figure 16: P ossib le Conformations of Thujopsene
With this assumption, the transition states 21_ and 22^ resem bling 2-II
and 2 -HI resp ectively, w ere considered (figure 17).
Since the addition of diborane to the double bond is c is and the rep lace­
ment of boron by hydroxyl in the oxidation proceeds with the retention of con-
-1 7 -
2-H
22
12
Figure 17: The Transition State
figuration
, the major alcohol product resulting from 21 would beJT , and
from 22 would be_12.
The sp ace-fillin g m olecular models clearly indicate that
in conformation 2-II, the bottom side of the m olecule (figure 17) is more hindered
due to the interference of the protons at the ring juncture, and also that in con­
formation jW II there is much le s s possibility of attack from the other side of
the 77-sy stem since that side of the double bond is hindered by the oxygen atom
and its neighboring atom s.
The product of this reaction was found a mixture of
exo alcohol 12^ and endo alcohol IT in the ratio of 28:72 (figure 18).
ports our suggestion that 2-H is the ground state conformation.
This sup­
-1 8 -
Ratio:
Figure 18: The Products From Hydroboration of 2.
CIS-8-OXABICYCLO [4. 3. 0] NONAN- 3 -ONE
Oxidation of the alcohols 3_1 and E2 by Jone's procedure gave a single
ketone c is-8 -o x a b icy clo [4 .3 . 0] nonan-3-one, (23), in alm ost quantitative yield.
When oxidizing the alcohols 11 and 12^ two methods had been attempted.
18 28
Brown's chrom ic acid-ether procedure ’
was tried and lead to a decomposed
product.
This type of oxidation was apparently too strong for alcohols from 2.
29
Jone's oxidation was found very satisfactory - sim ple to run, and gave high
y ield s.
The ketone 23_ on reduction with sodium borohydride afforded the exo
and endo alcohols 12 and 11_ in the ratio of 17:83, and with lithium aluminum
hydride in the ratio of 20:80 (table 3).
Table 3: R esults From Reduction of C is-8-oxabicyclo [ 4. 3. 0]
nonan-3-one.
Method of reduction
Product ratio
11 12
(1) NaBH4
83 : 17
(2) LiAlH4
80 : 20
It was first proposed ^
^ that the reactions of cy clic ketones with
m etal hydrides was governed by two opposing factors: (I) Steric Approach
Control, the ste r ic hindrance to approach of the reagent to the carbonyl function.
(2) Product Development Control, the stability of the final product.
In term s of
these two factors, it was proposed that the steric approach control predominated
34
33
in the reaction of hindered cyclic ketones , e . g . , 24(a) , (figure 19); and that
-2 0 the product development control predominated in the reduction of unhindered
31 33
cy clic ketones, e . g . , 24(b) '
(figure 19). U nless approach to one side of
the carbonyl group in a cy clic ketone was clearly much more hindered than
approach to the other sid e, the usual result of a metal hydride reduction was
the formation of a mixture of alcohols in which the m ore stable alcohol p re­
dominated35.
> I (Steric Approach
Control predominated)
(b): R1 = R2 = H
Rg = -H, -C Hg, -C(CHg)2 , -<SD>
2^6(b) ^ 1 (Product Development
Control predominated)
Figure 19: Steric Approach Control vs Product Development Control
It was proposed later35 33 that the reaction between cy clic ketones and
nucleophilic reagents such as m etal hydrides, were governed by the relative
36
37
magnitude of ste ric strain
and torsional strain
in the eclip sed reactant-like
transition state, as shown in Figure 20.
When the substituents on Cg and C5 of
the cyclohexanone ring w ere sm all, e . g . R1 = H, R2 = H, the steric strain in
transition state 27 was expected to be sm a ll, sm aller than the torsional strain
—2 1 —
SfeWc R
Figure 20: T orsional Strain vs Steric Strain in the Transition State
in transition state 28.
This resulted in the predominant formation of the equa­
torial alcohol 26_ (figure 19).
When the siz e of the substituents of
and Cg
in creased , the steric strain in 27 increased, and the torsional strain in 28 was
rem aining unchanged.
This led to the increasing proportion of axial alcohol 25_
in the product m ixture.
In the case of cis-8 -o x a b icy clo [4 .3 . 0]nonan-3-one, (23), the two
possible chair conformations 23-1 and 2 3 -II (figure 21) both indicated the p re­
dominant formation of endo alcohol T l , in term s of relative magnitude of ste ric
strain and torsional strain in transition sta tes.
In conformation 23-1, the New­
man projection clearly indicated that the c is -substituents on Cg and C5 in the
cyclohexanone m oiety w ere hydrogens.
The steric strain is expected to be
—
22 —
sm aller than the torsional strain.
In conformation 23-11, the substituents on C3
and C4 in the cyclohexanone moiety are bulky.
expected to be larger than the torsional strain.
T herefore, the steric strain is
In both c a se s , the attack of
metal hydride is favored from the le s s strained side and affords the predom i­
nant endo-alcohol I L
This theoretical prediction agrees with the observed data
shown in table 3.
0
Figure 21: P ossib le Conformations of 23^, and the P ossib le Approach
of the Metal Hydrides to the Carbonyl Function.
PA R T II
SYNTHESIS AND REACTIVITY OF
CIS-7, 7, 9, 9-TETRAMETHYL-8-OXABICYCLO [4 .3 . 0] NON-3-ENE
INTRODUCTION
While investigating the conformation of cis-8 -o x a b icy clo [4. 3. 0]n on -3en e, (2), one of the sim ila r system s was found to be very interesting.
The
backbone structure of 8-oxabicyclo [4 .3 . 0]non-3-ene with four methyl groups
added to the a and oc' carbons of the ether oxygen constructed the m olecule of
c is - 7 ,7 , 9, 9-tetram ethyl- 8 -oxab icyd o [ 4 .3 . 0] non-3-ene (3).
T hese four methyl
groups w ere expected to contribute to the conformation and the chem istry of the
whole m olecule.
MOLECULAR MODEL
By examining the sp ace-fillin g m olecular m odels of 3, one would observe
three possible conformations corresponding to that of 2_ (2-1, 2-II, and 2 -HI)
(figure 22).
Figure 22: P ossib le Conformations of C is -7 ,7 , 9, 9-tetram eth yl-8oxabicyclo [4.3. 0] non-3-ene.
-2 4 3-1 was the distorted pseudo-chair form , and 3-II and 3 -III w ere the two possible
boat form s.
One finds that the 77-electron s of the double bond at one side of the
m olecule are blocked and shielded by the methyl group(s) in both conformation
3-1 and 3 - i n . Yet in conformation 3-II the 77-electrons of the double bond are
freely open at both sid es of the m olecule.
SYNTHESIS
C is -7 ,7 , 9, 9-tetram ethyl-8-oxabicyclo [4 .3 . 0 ]n o n -3 -e n e , (3), was p re­
pared according to figure 23.
■a . Vacuum
Figure 23: Preparation of C is- 7 ,7 ,9 , 9-tetram eth yl-8-oxabicyclo
[4.3. 0] non-3-ene.
The com m ercially available anhydride IA was converted into the d iester
29 by methanol and acid.
Then, 29^ was reacted with a large e x c e ss (7.5 e q u iv .)
-2 5 of methylm agnesium iodide, the Grignard reagent, to give the c is-d io l 3£.
The interesting product, lactone 31, as evidenced by infrared spectroscopy,
could be obtained if only 2. 5 equiv. of methylmagnesium iodide was used for
d iester 2_9 (figure 24).
Figure 24: The Grignard Reaction of D im eth y l-cis-4 -cy clo h ex en e1 ,2 -di carboxyl ate.
The diol 30 readily dehydrated on distillation, in vacuo, and afforded
the bicyclic ether 3^ (figure 23).
Som etim es a mixture of two compounds with
the ratio of 30:70, as analyzed by g lc, was obtained when diol 3 £ was dehydra­
ted.
The major product was 3; the minor one, as analyzed by nm r, was s u s ­
pected to be the trans iso m er, 32^ (figure 25).
Further verification for this unreported trans isom er was not possible
due to the difficulties of separation encountered.
-2 6 -
Figure 25: C is - and T rans- 7 ,7 , 9, 9-tetram ethyl-8-oxabicyclo
[4 .3 . 0] non-3-ene.
NMR SPECTROSCOPIC DATA
The nmr spectrum of c is - 7 ,7 ,9 , 9-tetram eth yl-8-oxab icyclo [4.3. 0]
non -3-ene, (3), exhibits two singlets with equal intensity for the methyl groups
adjacent to the ether oxygen. (The full nmr spectrum of 3 is attached in Appendix
IV). This requires that Ra and Ra , share equivalent magnetic environm ents, as
must Rj3 and R^, (figure 22).
One expects to observe the spectrum exhibiting four sin glets for the four
methyl groups if 3-1 w ere the ground state conformation, since the four methyl
groups are all in different environments in 3-1.
This is not the case; th erefore,
3-1 is not the ground state conformation.
Though Ra and Ra ,, also R^ and R y,, share equivalent environments in
3 -n and 3 -III, the stereoch em istry of 3-II and 3-III are very much different from
each other.
T herefore, the conformation should be able to be rationalized with
the assistan ce of chem ical data.
-27
OXYMERCURATION
The oxym ercuration-dem ercuration of olefins has been reported to be
a convenient procedure for the Markovnikov hydration of carbon-carbon double
b o n d s ^ ’^ , and also to be free from skeletal rearrangem ent^9,
The
m echanism of m ercuration of olefins has been proposed to be via a m ercurinium
42-44
ion
, and the hydration stage of the initial m ercury interm ediate to be
41 45
occuring predominantly from the le s s hindered side of the m olecule ’
by a
tra n s-addition.
This hydration of double bond of 3 -II and 3 -III w ill lead to different pro­
duct or product m ixtu res, assum ing that the m echanism of trans-addition is
not changed.
From the sp ace-fillin g m olecular m odels of 3-III, one w ill observe,
very clearly, that the double bond is hindered from one side of the m olecule.
T herefore, only the other side of the double bond w ill form the mercurinium
ion interm ediate, then trans addition of entering water m olecule w ill lead to
the only product, the endo-alcohol 3 4 ,(figure 26).
Yet the sp ace-fillin g model of 3-II indicates that the double bond is
freely open for addition reaction from either side of the m olecule, with the
bottom side (figure 26) le s s free because of the presence of the two ring juncture hydrogens.
The m ercurinium ion interm ediate can form at either side
of the double bond, and then the hydration of the m ercurinium interm ediate.
In th is c a se , one might expect to observe a product m ixture of exo and endo
alcohols 33_ and 34.
The product mixture from the oxym ercuration-dem ercuration of 3_ was
analyzed by analytical g lc , and the chromatogram exhibited a single broad
unsym m etrical peak, with the sm aller slope present at the left side of the
peak (figure 27).
U sually a single sharp peak w ill be detected when a pure compound is
4Cz
y
V
H3COAcJ2.
h
3-1
H3 OAc
H
y ,1
CH3
H gO C TranS- <uU ition )
HjOAc
-Z3
HzO
/
A/ _ H r v v
(T ran S'j-aeUrh »n) ^
NaBHi-
NaBt
H^jZH3
34
HO"""
^ ch3
Figure 26: P ossib le Product or Product Mixture From Oxymercuration-dem ercuration of 3-II and 3-III.
-29
Ketcntion Time
Figure 27: The Observation of the Product Mixture From
Oxym ercuration-dem ercuration of 3^
analyzed by analytical glc with the right column chosen.
It is also
observed that a single broad peak will be detected when a mixture of two com ­
pounds with very close retention tim e is analyzed by glc.
When this mixture
has a 50:50 ratio, this broad peak usually is sym m etrical; when the ratio is not
50:50, this broad peak w ill be unsym m etrical.
The ratio of the two isom eric alcohols 33^ and 3 £ was found (30-40):(60-70),
when the chromatogram was analyzed by the method of triangulation (figure 27).
Though these two iso m ers w ere not further purified, due to the experim ental
difficulties encountered, infrared spectroscopy of the product mixture supported
the alcohol functionality.
Oxidizing this product mixture by Jone's reagent
(CrOy in H2SO4 ) showed the complete disappearance of the alcohol functionality
and the presence of a single ketone, as evidenced by analytical glc and infrared
spectroscopy.
A lso, the result of the elem ental analysis of the derivative of the
product mixture showed the correct com position (table 4).
The sharp melting
point of the derivative is not consistant with a product m ixture.
However, the
repeated purifications may have effectively removed one of the iso m ers.
-3 O—
Table 4: Report of Elem ental A nalysis of the 3 , 5-dinitrobenzoate
D erivative^6 of the Product Mixture From Oxymercuration of C is-7 , 7, 9, 9-tetram eth yl-8-oxab icyclo [4. 3. 0]
non -3-enea ’ c
Composition
%C
%H
%N
%o
Calculated
58.16
6.17
7 .1 4
28.54
Found
57.88
5.9 3
-
-
a.
E m pirical formula: C19H ^ N 2O7
b.
Color of this crystal is silvery white
c.
R ecrystallized from ethanol-w ater. Melting point
is 143-144. 5°C , m easured by Fisher-Johns
melting point apparatus.
Based on the information from the m olecular m odels, the glc analysis,
the oxidation of the alcohol m ixture, and the report of elem ental analysis of
the alcohol derivative, this researcher proposed that the conform er 3-II is
the ground state conformation.
It is of in terest to mention a qualitative result: W hereas we note alm ost
im m ediate reaction of 2_ under conditions of oxym ercuration, 3^ appeared to
react quite slow ly.
This may have som e significance and is consistent with
nmr data to be presented later.
NMR STUDY FOR THE LONG-RANGE ELECTRONIC PARTICIPATION
8 9
After Mundy and Otzenberger ' reported the effect of long-range
electronic participation from the nonbonded electrons of the ether oxygen to_
the 77-electron s of the double bond in system 2, this resea rch er found that it
was equally interesting to investigate the effect of the long-range electronic
-3 1 participation from the 77-sy ste m of the double bond to the non-bonded electrons
of the ether oxygen in the system s 2_ and_3 (figure 28).
Figure 28: The Long-range E lectronic Participation Between the
77-system of the Double Bond and the Nonbonded E lec­
trons of the Oxygen in_2.
The nmr study was chosen for this resea rch and was started by com par­
ing the nmr spectra of system s 2 in two different solvents; de ute roc hi or of or m ,
and a mixture of deuterochloroform and deuterotrifluoroacetic acid with a
50:50 ratio.
A deshielding effect was observed for the protons adjacent to the
oxygen atom, and also for the other protons in this m olecule.
Then, the same
experim ent was carried on to the system 3^. The deshielding effect to the pro­
tons of the double bond in 3^was found to be sm aller than that in system 2^
(tables 5 and 6).
This observation was rationalized by the difference of the long-range
electron ic participation between system s 2_ and JS.
Conformer 2-II (figure 10) could convert to conform er 2 -III to allow the
77-electron s of the double bond to stabilize any influence from the approaching
-3 2 Table 5: The Observed Chemical Shifts of Protons in 2.
Chemical Shift (6)
Compound
Iro d$HCb
Solvent
HH
CO
2
CDClg
CDCl3
i
H
5 .5 9
3 .6 7
2 .3 5
2.12
5.67
3 .8 8
2.47
2 .1 5
+ 0. 08
+0.21
+0.12
+0. 0 3
CF3COOD
Change of Chemical
Shifta
(A 6 )
a.
(+) sign represents the increase in 6 value; downfield 6 value.
(-) sign represents the d ecrease in 6 value; upfield 6 value.
Table 6: The Observed Chemical Shifts of Hydrogens in 3.
Chemical Shift (6 )
Compound
C D C lg
CS,
CDClo
ay
%
Solvent
a
HjC CH3
5 .6 9
2.13
1.27
1.14
5.72
2.2 0
1.3 8
1.26
+0. 03
+0. 07
+0.11
+0.12
3
Change of Chemical
shift
(AS)
-3:3positive charge to the non-bonded electrons of the oxygen.
T herefore, the
deshielding effect due to the presence of the positive charge influenced the
protons of the double bond more than that without the long-range electronic
participation.
The larger deshielding effect to the protons of the alkene than
that to the other protons on the cyclohexene moiety in 2 supported this postula­
tion clearly (table 5).
On the other hand, though the conformation 3-II (figure 22) could also
convert to conform er 3 -III; the methyl groups adjacent to the oxygen blocked
the long-range electronic participation.
Examination of m olecular m odels
support th is.
In this c a se, the deshielding effect to the hydrogens of the double bond
would be the sm a llest among all the hydrogens in system 3^, since they w ere
the farthest hydrogens to the oxygen.
The observation (table 6) again supported
th is proposal.
To further verify this suggestion, the sam e experim ent was carried on
47
to the corresponding saturated system , cis-8 -o x a b icy clo [4 .3 . 0] nonane , (36),
(figure 29).
It was again noted that the farthest hydrogens to the oxygen was
36
Figure 29: The Structure of C is-8-oxabicyclo [4.3. 0] nonane,
influenced the lea st when 36 was in an acidic solvent (table 7).
While carrying on these experim ents, the effect of the concentration of
the sam ple in the solvent mixture was investigated and found independent
to the deshielding effect.
Compound 3^was used for the investigation.
The
ratio of deuterochloroform and deuterotrifluoroacetic acid was carefully kept
-3 4 Table 7: The Observed Chemical Shifts of Hydrogens in 36.
Chemical Shift 16 )
Compound
Solvent
o? cb
H
CDCl3
Co
CDCl3 =1
CF3 COOD
3 .6 9
2 .2 1
1.48
3 .9 0
2.3 6
1.51
+0.21
+0.15
+0. 03
36
Change of Chemical
shift
(A 6)
the sam e, i .e . one to one, during all the investigation.
in table 8.
The resu lts were shown
-3 5 Table 8: The Observed Independence of Deshielding Effect to the
Concentration of the Sample in Acidic Solvent.
Chemical Shifts (6 )
Compound
Concentra­
tion^'
I
5.72
2.2 0
1.3 8
1.26
1 /2
5.72
2.2 0
1 .3 8
1.26
1/8
5.7 2
2.20
1 .3 8
1.26
HjC CHj
3_
a.
The solvent is a mixture of CDCl3 and CF3COOD, with
a 50:50 ratio.
b.
The actual concentration of 3^ in the solvent was not ca l­
culated and was tentatively assigned as I , then diluted
to half, and then one-eighth of this concentration.
P A R T III
CIS-N-SUBSTITUTED-8-AZABICYCLO [4 .3 . 0] N 0N -3-E N E SYSTEMS
INTRODUCTION
"The use of analogies — or gviessed-aboiit analogies — is
probably s till one of the main ch aracteristics of organic
chem istry.
Hopefully, this method offers the advantage that
we may proceed from a group of ’ sim p le', w ell-estab lish ed
data toward slightly different or m ore complex situations.
In fact, this is done not only in preparative organic chem ­
istr y , but also in the application of quantum m echanics.
In
such an approach-by-analogy, we have to use intuitive co r­
rection s and extrapolations, the main difficulty being to
predict or a s s e s s the differences between our analogs and
the new sy stem s to be co n sid ered ."
— E. C. Kooyman
48
From the sam e attitude and philosophy as the above quotation, this part
was carried on to the nitrogen-containing heterocyclic compounds.
Several cis-N -su b stitu ted -8 -a za b icy clo [4.3. 0]non-3-ene sy stem s, 4,
w ere studied (figure 30).
_
O f
38
C O -
CH2CH2CH,
R '= < 5 > , -CH2CH2CH3
R
= H ,J>
Figure 30: The Structures of C is-N -substituted-8-azab icyclo
[4. 3. 0] non-3-ene System s.
-3 7 SYNTHESIS
The general synthesis of the cis-N -su b stitu ted -8-azab icyclo [4.3. 0]
non-3-ene system s w ere outlined in figure 31.
Figure 31: The Preparation of C is-N -substituted-8-azab icyclo
[4. 3. 0]non-3-ene System s.
The quaternary methiodide salts of the cyclic tertiary amines were
prepared according to figure 32.
Figure 32: The Preparation of the Quaternary Methiodide Salt
of the C yclic T ertiary A m ines.
-3 8 NMR STUDY FOR THE LONG-RANGE ELECTRONIC PARTICIPATION
The nmr study of the effect of long-range electronic participation was
carried out in the sam e method as that used for the oxygen-containing hetero­
cy clic analogues.
After the com parison of the nmr spectra of 37_in deuterochloroform ,
and the solvent mixture of deuterochloroform and deuterotrifluoroacetic
acid
in the ratio of 50:50, the deshielding effects to the protons in T7 were observed
as tabulated in table 9.
Sim ilar experim ents w ere carried out on the saturated analogy of 37,
cis-N -p h en yl-8-azab icyclo [ 4 .3 . 0] nonane, (45), (figure 33).
The deshielding
effects to the hydrogens in 45_ are tabulated in table 10.
Figure 33: The Ci s - 8 -phenyl- 8 -a z abicyclo [4 .3 . 0] nonane and its
Quaternary Methiodide Salt.
For further investigation of the influence from the TT-electrons of the
double bond to the nitrogen, the quaternary methiodide sa lts of 37_ and 45 were
prepared for the sam e nmr experim ents.
and table 12 resp ectively.
The results are shown in table 11
One observes the deshielding effect on the hydro­
gens of the double bond from the positive charge of the nitrogen in_42, while
in 46, the hydrogens on the cyclohexene m oiety w ere not de shielded at all.
Table 9: The Observed Chem ical Shifts of Protons in 37.
Chem ical Shift (6)
HH
Compound
OX2>
37_
Solvent
CDCl3
*
Dp: X5 KH
7.1 6
6 .52
P
i
$
5.62
3 .2 0
2.4 0
2.1 2
5.88
3.9 8
2.99
2.2 9
+0.26
+0.78
+0.59
+0.17
(6. 84)
CDCl3 =1
CF3COOD
Change of Chemical
Shift ( AG)
7 .5 4
+0.38
+1.02
(+0 .70)
Table 10: The Observed Chemical Shifts of Some of the
Protons in 45^
_ _ _ _ _ _ _ _ _ _ _ _ I_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Chemical Shift3 ( 6 )
Compound
Solvent
0 3 - 0
H
7 .1 5
(6. 88)
C C H O
CDCl3
CF3COOD ]
45
Change of Chemical
Shift ( AS )
a.
H
6.61
7 .5 0
+0.35
1.48
1.57
+0. 89
+0. 09
(+0. 62)
The chem ical shifts of the other hydrogens in 45 were not com pletely
identified due to its com plexity of overlapping peaks.
-4 0 -
CDCl3
0 3 0 "
—
41
Table 11: The Observed Chemical Shifts of Some of the Hydrogens
in 37 and 42.
Chemical Shifta (6 )
Compound
IOS
Solvent
(X)-O
03??-
7.16
6.52
5.62
7.97
7.60
5.98
+0.81
+1.08
+0.36
CDCl3
Change of Chemical Shift (A5)
Table 12: The Observed Chemical Shifts of Some of the Protons
in 45 and 46.
Chemical Shifta (5 )
X
Compound
Solvent
X
7 .1 5
6.61
1.48
7 .8 8
7.56
1.46
+0.73
+0.95
-0 .0 2
CDCl3
*
Change of Chemical Shift ( AS)
a.
The other parts of the nmr spectra were not clearly designated
due to the com plexity of the peaks.
-4 2 Another interesting nitrogen-containing heterocyclic sy stem , 313, was
also investigated by the sam e nmr experim ents.
The observations are tabula­
ted in table 13.
Table 13: The Observed Chemical Shifts of Some of the Hydrogens
in 38.
Chemical Shifta ( 6 )
Compound
( T ^ Q - C H 2CH2CH3
38
Solvent
IOj
CDCl3
5.74
0. 87
5.73
0. 97
-0 . Ol
+0.10
CDCl3 =1
CF3 COOD
Change of Chemical
Shift ( AS )
a.
^ N -C -C -C H 3
The chem ical shifts of the other hydrogens in
system 38 w ere not com pletely identified due
to the complexity of the overlapping of the peaks.
The deshielding effect was observed for all but the hydrogens of the
double bond in system 38_. For further understanding, the nmr spectra of 38
and its quarternary methodide salt 43^, w ere compared (table 14).
-4 3 Table 14: The Observed Chemical Shifts of Some of the Protons
in 38^ and 43.
Chemical Shifta (6)
Compound
^ Q l - C H 2CHaCHj
UDj
Solvent
38
^ Q h-C-C-CH3
5.74
0. 87
5.95
I . 05
+0.21
+0.18
CDCl3
COrfT'e
Change of Chemical Shift ( AS)
a.
Same as that of Table 13.
The hydrogens of the double bond in quaternary salt 43_ w ere found also
to be deshielded, as w ere the other hydrogens.
T hese phenomena would be explained by the preferential nitrogen in ver­
sion of 38-II (figure 34).
Some techniques and observations had been reported for investigating
the conformation of the non-bonded electrons of the nitrogen atom.
Bohlman ^ and H am low ^ reported the study of the conformation of the
non-bonded electrons of nitrogen in the quinolizidine ring system (figure 35).
B ecause of the stereoch em istry of the ring fusion, Hc is trans to the nonbonded electrons on the nitrogen atom.
The nmr spectrum of 47_ shows that
the chem ical shift between Ha and Hfi is 0. 93 ppm.
The proton (Ha ) which is
-4 4 CH2CH2CHj
^CH 2CH2CU3
38-1
^ c V H jC
,,..'CHjCHjOi =
CD
----------^
.X i-
—
3 8 -n
Figure 34: P ossible Conformations of the Nitrogen Inversion of
System 38.
anti-coplanar to the non-bonded electrons of nitrogen atom appears upfield
from Hb . When £7 was protonated to 48, the chem ical shift between Ha and
Hg d ecreases to 0. 4 -0 .5 ppm, a difference that is typical for "normal"
axial vs equatorial protons.
47
48
Figure 35: The Quinolizidine Ring System
-4 5 B ro is51 and R oberts52 have reported the behavior of the nitrogen atom
in the aziridine ring system (figure 36).
When the inversion between 49-1 and
Figure 36: The Aziridine System
49-11 is rapid, then all four of the ring protons are expected to be magnetically
equivalent.
On the other hand, if the inversion process is slow enough, the
ring proton w ill appear as an AgBg sy stem .
It has been found that the barrier
to nitrogen inversion in the s e r ie s N -m ethyl, N -ethyl, N -isopropyl, and N -te r tbutyl aziridine d ecrea ses with increasing siz e of substituents on nitrogen atom.
53
Rauk reported the inversion b arriers of N -substituted-2,2-dim ethylaziridine system s (figure 37).
V ,
When the substituents was methyl group, the
CH3
Inversion barrier
R
R = CH3
18-20. 5 kcal/m ole
R = C6H5
11. 2 kcal/m ole
Figure 37: The N -substituted-2, 2-dim ethylaziridine System s
-4 6 energy for inversion was larger than that for the phenyl group.
F e lix 53, 54 reported that the conversion of a bicyclic system SIl (figure
38).
Due to the steric crowding in the c is conformation, this m olecule pre­
ferred to convert form c i s - to tra n s- conformation.
Figure 38: The C is-7 -ch lo ro -7 -a za b icy clo [4 .1. 0] heptane System
Based on the above information and the factors that affect the magnitude
53
of inversion barrier , one expects to predict that, besides the steric factor,
the repulsion between the nonbonded electrons of nitrogen atom and the rr-system of the alkene also contribute to the preferential conformation of the non­
bonded electrons on nitrogen atom in 38-II (figure 34).
In 38-1, one expects to observe the long -range electronic participation
from the 77-sy stem of the alkene to the nonbonded electrons of nitrogen atom.
This electronic participation w ill cause the deshielding effect to the hydrogens
on the double bond, which is not observed.
In 38-11, the possibility of this
long-range electronic participation w ill be totally blocked.
In this case, the
hydrogens on the double bond w ill not be de shielded, as was observed.
When 38 was converted to its quarternary salt, 43^, the nitrogen atom
carried positive charge, which influenced all the hydrogens in the m olecule.
—
47 —
This rationalized the existen ce of the deshielding effect to the hydrogens of the
double bond in 43, and the non-existence of the deshielding effect to the c o r r e s ­
ponding hydrogens in 38, (tables 13 and 14).
F or sim plifying the runr spectrum of 38, the deuterated analogy j?9 was
prepared and studied sim ila rly .
Yet the nmr spectrum of 39 s till exhibited the
com plex of overlapping peaks (tables 15 and 16).
Table 15: The Chemical Shifts of Some of the Protons in 39.
Chemical Shifta ( 6 )
Compound
Solvent
CDCl3
I ^
C
ch2OI2CH3
39
CDCl3
CF3COOD 1
Change of Chemical
Shift ( A 6)
a.
IOj
&
N-C-C-CH3
n s ,
5.77
0.87
5.76
0.99
-0 . Ol
+0.12
The chem ical shift of the other hydrogens w ere
not com pletely identified due to the com plicated
overlapping of peaks
-4 8 -
Table 16: The Observed Chemical Shifts of Some of the Protons
in 39 and 44.
Chemical Shifta (6)
Compound
Solvent
x
d
DD
(T ^ N -C H g C H g C ^
39
5.77
0. 87
5.9 4
1.05
+0.17
+0.18
CDClg
^
V
( i ^ N ^ V /C H 2CH2CH3
*
Change of Chemical Shift ( A 6)
a.
The chem ical shift of the other hydrogens w ere not
com pletely identified due to the complicated over­
lapping of peaks.
Since all the above nmr studies are carried out in deuterochloroform ,
and the mixture of deuterochloroform and deuterotrifluoroacetic acid, one
might expect to investigate the effect of the ratio of the solvent mixture.
The
experim ent of the effect of the solvent ratio clearly indicates that the deshield­
ing effect in creases with the increasing acidity of the solvent (table 17).
Table 17: The nmr Study of the Dependence of the Deshielding
Effect to the Acidity of the Solvent.
Chemical Shift ( 6 )
Sample
030
Solventa
C on cen ­
tration
of
Sample
CDCl3 =1
CF3COOD
I
7 .5 4
5.88
3.9 8
2.9 9
2.2 9
2 /5
7 .5 4
5.8 9
4. 00
3 .0 0
2 .3 1
±0. OO
+0. Ol
+0. 02
+0. 01
+0.02
CDCl3 =i
CF3COOD
37
Change of Chemical Shift ( A6)
a.
HM
.
W $
The solvent m ixture of CDCl3 and CF3COOD in the ratio of 1:4 was
prepared by diluting the solvent mixture in the ratio of 1:1 by three
m ore equivalents of CFgC OOD.
b. The actual concentration of-the sam ple in the solvent is not calculated,
and was tentatively assigned as I, and then was diluted to 2 /5 .
-5 0 -
RE LATION TO THE CORRESPONDING OXYGEN SYSTEM
' From the' rimr study of the de shielding effect from the oxygen- and
nitrogen-containing heterocyclic system s sim ila r to !Lwhen present in an acidic
solvent, one resem blance between these two sy stem s was noticed.
The en­
hancement of the de shielding effect to the hydrogens of the double bond was
detected in both system s when the long-range electronic participation from the
17-sy ste m of the double bond to the non-bonded electrons of the heteroatom
existed .
When this electronic participation was blocked, the de shielding effect
to the hydrogens of the double bond was the sm a llest among that to all the
hydrogens in the m olecule, due to the factor that the hydrogens of the double
bond w ere the farthest to the heteroatom in oxygen-containing sy stem s.
In
nitrogen-containing sy stem s, som etim es the hydrogens of the double bond w ere
not even de shielded when the long-range electron ic participation was blocked.
It is probably due to the difference of the nonbonded electrons in these two
sy stem s.
When nitrogen compounds w ere studied, the nitrogen inversion must be
also investigated, since the conformation of the nonbonded electrons on nitrogen
atom would influence the chem istry of the whole m olecule, as demonstrated by
38 and 37.
In sum m ary, this type of resea rch can offer much valuable information,
though much of it is still not w ell understood at this point.
Further research
and investigation toward th is end is recom m ended, not only for the nitrogenand oxygen-containing sy stem s, but also for the other heterocyclic system s
with nonbonded electrons on the heteroatom .
Further resea rch should include
low -tem perature nmr stud ies, and p ossible m olecular orbital calculations.
EXPERIMENTAL
GENERAL INFORMATION
(1) The analytical data available in th is report w ere analyzed by the following
instrum ents or company:
,
Elem ental A n alysis: By C hem alytics, I n c ., Tem pe, Arizona
Gas Liquid Chromatographic a n a ly sis:
(a) F&M B iom edical Gas Chromatograph Model 400
(b) Aerograph Autoprep Model A -700
The columns used are described in Appendix n .
Infrared Spectra (IB): Beckman IR-5A Infrared Spectrophotometer, using
polystyrene as the standard.
Nuclear Magnetic Resonance Spectra (NMR):
Varian A -60 Analytical NMR Spectrom eter, using tetram ethylsilane
(TMS) as an internal standard, and the deuterochloroform as the solvent
u n less otherw ise indicated.
(2) The m elting points (mp) and boiling points (bp) are uncorrected and are in
d egrees centigrade.
(3) P r e ssu r e s are reported in mm of m ercury (e.g . bp^ 85°C indicates the
boiling point is 85°C at the pressu re of 7 mm of m ercury).
PART I
PREPARATION OF C IS -1 ,2 ,3, G-TETRAHYDROPHTHALYL ALCOHOL55, (15):
A solution of c i s - 1 , 2 ,3 ,6 -tetrahydrophthalic anhydride, 14, (15.2 g,
0 . 1 m ole), in approximately 100 m l of anhydrous tetrahydrofurana was added
over a period of tw o hours to a mixture of lithium aluminum hydride*3 (4.18 g,
0 .1 1 m ole) in 350 m l of anhydrous ether.
The reaction w as carried out in a
5 lite r , 3 necked flask equipped with a reflux condenser, m echanical stir r e r ,
addition funnel and a m ercury bubbler for isolation from the atm osphere.
After
-5 2 the reaction ,was com plete, the mixture was refluxed for two hours.
A saturated
solution of R ochelle Salts was added dropwise for work up until no further r e a c ­
tion was noted.
The reaction mixture was allowed to settle , and the liquid was
decanted and concentrated.
w as refluxed.
Methanol was added to the sa lts and this mixture
Then the methanol solution was separated and added to the fir st
crude product m ixture.
This o il was d istilled to give a viscou s c o lo rless c is
diol 15 (9. 95 g , 70% yield).
CC
bp0 5 126-129°C (Literature
: bp12 165-170°C)
Infrared - 3200, 3000, 2850, 1650, 1430, 1320, 1170, 1095, 1025,
975, 955, and 925 cm - *
mnr - 2.015 (broad peak, 6H), 3 .56 (multiplet, 4H), 4.066 (sharp
singlet, 2H), 5.56 (2H).
a.
Anhydrous ether could be also used as the solvent for anhydride 14.
But the solubility of 14 in ether was much low er than that in te tr a hydrofuran. A lso due to the in crease solubility of anhydride 1 £ in
tetrahydrofuran, th is reaction can be run on a 0 .5 m ole scale by
using only 250 ml of tetrahydrofuran for the anhydride solution.
b. When the lithium aluminum hydride was not used in e x ce ss or was
im pure, the lactone 16 would be obtained. Further reduction of
lactone 16^ with lithium aluminum hydride would give c is diol 15
with quantitative yield. The boiling point of lactone 16 was 129132°C at 10 mm Hg.
PREPARATION OF CIS-8-OXABICYCLO [4 .3 . 0] NON-3-ENE, (2)1
A solution of c i s - 1 , 2 , 3 , 6-tetrahydrophthalyl alcohol, 15, (7 .1 g, 0.05
m ole) in pyridine (10 ml) was heated to reflux.
A solution of p-toluenesulfonyl
chloride (14 g, 0.07 m ole) in pyridine (10 m l) was then added dropwise with
stirrin g.
The reaction mixture was further refluxed for one hour, after the
addition was com plete.
The solution was cooled and poured into an ice-su lfu ric
acid bath to neutralize the pyridine.
This aqueous mixture was extracted with
-5 3 ether, and the ether extracts w ere dried over anhydrous magnesium sulfate.
D istillation yielded 5 .2 1 g of the c o lo rless liquid product 2_ (84% yield).
bp1Q 54-56°C (Literature^: bp^g 63-64°C)
Infrared - 3000, 2910, 2840, 1650, 1490, 1455, 1088, 1053, 1018,
956, 940, 899, 882, 717, and 653 cm -1
nmr (attached in Appendix IV) - 2 .126 (4H), 2.366 (2H), 3. 676 (4H),
5.606 (2H)
glc data - see table 18
QQ
OXYMERCURATION-DEMERCURATION
4f)
’
OF ALKENES
The alkene (0. 01 m ole) was added to a stirred m ixture of m ercuric
acetate (3.2 g, 0 .0 1 m ole) in aqueous tetrahydrofuran (20 m l, in the ratio of
50:50) at room tem perature. The reaction mixture was stirred for 15 minutes
after the yellow color had disappeared.
Potassium hydroxide solution (10 m l,
SM) was then added, followed by a sodium borohydride solution (0.19 g of NaBH^
in 10 m l of SM KOH). The m ercury was allowed to precipitate., and then 10 ml
of saturated sodium chloride solution was added. This m ixture was extracted
with methylene chloride, and the extracts w ere dried over anhydrous magnesium
sulfate, and then concentrated for further purification.
OXYMERCURATION-DEMERCURATION OF CIS-8-OXABICYCLO[ 4 . 3 . 0 ]NONS-E N E , (2)a
The usual procedure was carried out with the following quantities of
reactants; 2_ (1.24 g, 0. 01 m ole), m ercuric acetate (3.2 g, 0. 01 m ole), THF
(10 m l), water (10 m l), SM potassium hydroxide (10 m l), sodium borohydride
solution (0.19 g of NaBH4 in 10 ml of SM potassium hydroxide), and saturated
salt solution (10 m l).
D istillation afforded a c o lo rless liquid with boiling point 149-152°C at
18 mm Hg (1 .2 g, 84.4% yield).
This m ixture of the exo and endo alcohols 12^
-5 4 b c
and 11, in the ratio of 24:76 ’ , was separated by the preparative gas chrom­
atography with a carbowax 20M column.
The gas chromatographic data w ere
tabulated in table 18.
The infrared and nmr spectroscopic data of the major alcohol, c is - 8 oxabicyclo [4 . 3. 0] nonan-3-ol-endo^, (11), was shown in the following:
Infrared - 3320, 2900, 2840, 1485, 1450, 1365, 1197, 1070, 1047,
1020, 1000, 940, 925, 885, and 715 cm -1
n m r - 1 . 2 - 1 . 9 6 (6H), I . 9 -2 .5 6 (2H), 2.736 (sharp sin glet, 1H),
3 .3 -4 .0 6 (multiplet, 5H)
glc data - see-table 18 and table 19
a. This reaction was repeated by this research er
b.
Average of three runs
c.
R. D. Otzenberger reported the ratio as 1:3 (R eferences 8 and 9)
d.
This alcohol can also be prepared by the stereo sp ecific synthesis
outlined in figure 39.
0
0
O
HO'""
Figure 39: Stereospecific Synthesis of cis-8 -o x a b icy clo [4 .3 . 0]nonan3-ol-en d o.
-5 5 HYDROBORATION
57 58
’
OF CIS-8-OXA-BICYCLO [4. 3. 0]N O N -3-EN E, (2)
The alkene 2 (3.6 g , 0. 029 m ole) w as dissolved in 17 ml of dry diglym e,
to which sodium borohydride (1 .51 g, 0. 04 m ole) was added.
m ixture was stirred under nitrogen atm osphere at 20°C.
ether ate (3 m l, "99% pure) w as added dropw ise.
stirred for 30 min.
The reaction
Borontrifluoride
The reaction mixture was
-
A solution of 2N NaOH (3.5 ml) was added dropwise
followed by 3 .5 m l of 30% hydrogen peroxide at 20-25°C .
The reaction m ix­
ture was stirred for another hour, then extracted by ether and washed by d is ­
tilled w ater. The resulting crude alcohol mixture was compared with the known
9
products by analytical g lc with the carbowax 2OM column. The ratio of the
exo and endo alcohols 12 and 11 in the m ixture was found 28 to 72*.
g lc data - s e e table 18 and table 19
JONEfS OXIDATION
AND (12)
29
OF THE CIS-8-OXABICYCLO [4.. 3. 0]NONAN-3-OLS, (11)
The alcohol m ixture of 11 and 12_, (0.02 m ole, 2 .8 4 g) was dissolved in
acetone (20 m l) in an E rlenm eyer flask which was placed in a water bath so as
to maintain the reaction mixture at 25°C.
To th is was added dropwise the
Jones reagent (13.36 g CrOg in 12 ml concentrated HgSO^., then diluted to 50 m l
with HgO) until an orange-brown color rem ained.
The reaction mixture was
extracted with methylene chloride, and the extracts w ere dried over anhydrous
m agnesium sulfate, and then concentrated.
D istillation afforded the co lo rless
liquid ketone (99% yield),
bpiy 134-137°C
Infrared** - 2910(V. S .), 2840(V. S . ), 1720(V .S.), 1645, 1480, 1455,
*The average of three runs
**(V. S. -very strong; 8-strong)
Table 18: The Relative Retention Tim e of Compounds in System 2.
Compound
Retention tim ea »^
(min)
03.Co
hoJ
C
D
JX°
2
23
12
11
3 .5
2 3 .1
3 2 .9
35 .8
a.
The average of five injections.
b.
Data obtained from Aerograph Autoprep Model A-700 gas
chromatograph, with carbowax 2OM column at 170°C , and
with flow rate of 120 m l/m in.
Figure 40: The Observation From the glc Analysis of Compounds
in Table 18.
Table 19: The Observed Yield of Reactions From Compounds in
Table 18.
Reaction
O xym ercur- Hydrobor- Jone's Oxi­
ation of 2
ation of 2 dation of 12
and 11
Yield a ’ b
94. 5%
95.8%
100%
NaBH4
Reduction
of 23
99. 0%
LiAlH4
Reduction
of 23
100%
a.
Analyzed by F&M Model 400 Biom edical Gas Chromatography,
with a d isc integrator.
b.
Average of two to three runs.
-5 7 —
1420, 1360, 1350, 1325, 1300, 1240, 1200, 1115, 1095,
1080(S), 1070(8), 1045(8), 1025(8), 975 , 950 , 927(8),
893, 885, 741, 717, 692, 660 cm"1
glc data - se e table 18 and table 19
SODIUM BOROHYDRIDE REDUCTION OF CIS-8-OXABICYCLO [4. 3. 0]NONAN
- 3 -ONE, (23)
The solution of ketone 23_ (1 .4 g, 0. 01 m ole) in absolute methanol (10 m l)
w as added dropwise to a stirrin g solution of NaBH4 (0.28 g, 0. 0074 m ole) in
absolute methanol (10 m l).
After NaBH4 disappeared, another 0 . 1 g (0. 0026
m ole) of NaBH4 was added, stirred for 15 m in ., then the methanol was rem ov­
ed, and 3 ml of HgO was added.
The reaction mixture was extracted with
methylene chloride, and the extracts w ere dried over anhydrous magnesium
sulfate and concentrated.
The resulting crude alcohol mixture was compared with the known pro­
ducts (prepared according to either p. 53 or p. 55 ) by analytical g lc.
of the exo and endo alcohol, .12 and 11, was found 17:83*.
The ratio
The yield was shown
in table 19.
LITHIUM ALUMINUM HYDRIDE REDUCTION OF CI8-8-OXABICYCLO [4. 3. 0]
NONAN-3 -O N E, (23)
A solution of ketone 2j3 (1.4 g , 0. 01 m ole) in approximately 20 ml of
anhydrous ether was added over a period of two hours to a m ixture of lithium
aluminum hydride (0.38 g, 0 .0 1 m ole) in 15 m l of anhydrous ether.
The rea c­
tion was carried out in a round bottom flask fitted with a m agnetic stirring bar,
a reflux condenser, an addition funnel and a m ercury bubbler for isolation from
the atm osphere.
for one hour.
After the reaction was com plete, the m ixture w as refluxed
A saturated solution of R ochelle Salts was added dropwise for
work up until no further reaction was noted.
*The average of two runs.
The liquid was separated from
-58the solid sa lts by filtration, and washed by d istilled w ater, then dried over
anhydrous m agnesium sulfate, and then concentrated by using a rotary evapor­
ator. The resulting crude alcohol mixture was compared with the known pro­
ducts (prepared according to either p. 53 or p. 55) by analytical g lc.
of the exo and endo alcohols; 12 and 3J, was found 20:80*.
shown in table 19.
*The average of two runs
The ratio
The yield was
PART II
PREPARATION OF DIMETHYL CIS- £ -TETRAHYDROPHTHALATE1 ° 5^9)
Concentrated sulfuric acid (4„ 9 g , 0. 05 M) was fir s t carefully added to
anhydrous methanol (256 g, 8 M), and c i s - 1 , 2 , 3 , 6-tetrahydrophthalic anhydride,
14 (152 g, 1M), was then added, and the .mixture was refluxed for 18 hours.
A fter cooling, 5. 3 g of anhydrous NagCOg is added to neutralize the sulfuric
acid.
The methanol solution was separated by filtration, and then distilled.
The d istilled c is d ie ste r, 29, is a clear c o lo rless liquid (178.2 g, 90% yield).
bP l4 - l5 135-iL38° c (Literature5 8 : bp2o 141. 5-142°C )
PREPARATION OF C IS -a, Ce, a.', a r-TETRAMETHYL-4-CYCLOHEXENE-l, 2 DIMETHANOL59’ 6(), (30)
The methyl iodide (71.0 g, 0 .5 m ole) was added dropwise to a stirring
anhydrous ether solution of magnesium (12.2 g, 0 .5 0 g-atom ) to prepare the
cL b
Grignard reagent, m ethylm agneslum iodide ’ . To this was added dropwise an
anhydrous ether solution of 1 3 .2 g (0. 0666 m ole) of dimethyl c is - 4 -cyclohexen e1 , 2-dicarboxylate, 29, and the mixture was stirred at room tem perature for 19
hours.
Saturated ammonium chloride solution (125 ml) was added dropwise, and
the m ixture w as filtered .
The aqueous layer was extracted with ether, and the
combined ether la y ers w ere dried over anhydrous m agnesium sulfate.
The
ether w as rem oved by using a rotary evaporator to leave a slightly brown solid .
R ecrystallization from m ethanol-w ater afforded 10 .2 g of white crystals (77.2%
yield).
a.
Som etim es heating th is mixture gently was required to initiate
the reaction
b.
If the m ethyl m agnesium iodide was not used in e x c e s s , the lactone
31 would be obtained. The m elting point of lactone Tl was 67-68°C,.
nmr - 1.386 and 1.426 (2CH3 ), 1 .9 0 -2 .5 7 6 ’ and 5 .7 5 -5 . 806 (CH=CH)
-6 0 mp = 120-121°C (Literature59: mp = 119. 5 -1 2 0 .5°C)
(Literature60: mp = 122-123°C)
nmr - 1306 and 1.366 (4CH3), 2.196 (-CH2 ), 4.076 (-OH), and
5.676 (CH=CH)
PREPARATION OF C IS -7,7, 9, 9-TETRAMETHYL-8-OXABICYCLO [4 .3 . 0] NON
-3-E N E 59’ 60, 0
D istillation of diol 3£ at 20 mm using a bath temperature of 150-160°C
gave the c i s - 7 ,7 ,9 , 9-tetram ethyl- 8 -oxabicyc lo [4 .3 . 0]n on -3-en e, ( 3 ) \
bp20 94-96°C
(Literature59: bp2 0 9 7 .5 -9 8 . 5°C)
(Literature60; bpiQ 74-75°C)
Infrared* - 2950(S), 2900(S), 1665, 1465, 1445, 1380(S), 1365(S),
1300, 1270(S), 1230, 1210(S), 1190, 1160, 1136 (S), 1107,
1075, 1002, 986(S), 970(S), 952, 937, 888(S), 870, 820(S),
751, 712(S), 660(B), and 642 cm"1
nmr (attached in Appendix IV) - 1 . 146 and I. 276 (4CHg), 2.136 (6H)
and 5. 696 (CH=CH)
glc data - see table 20 and figure 42
a.
Som etim es, a mixture of two compounds with the ratio of 30:70,
as analyzed by g lc , was obtained (figure 39). The major component
of th is mixture was cy clic alkene 3_, the minor component was
suspected the tra n s-iso m er 32^
*(S = strong peak)
R eten tion
Time
Figure 41: The Observation of the Product Mixture from Dehydration of 30.
-6 1 OXYMERCURATION OF CIS-7, 7, 9, 9-TETRAMETHYL-8-OXA-BICYCLO
[4.3.01N O N -3-E N E , (3)
The usual procedure was carried out with the following quantities of
reactants: 3^ (I. 80 g, 0. Ol m ole), m ercuric acetate (3.2 g, 0. 01 m ole), THF
(10 m l), w ater (10 m l), SM potassium hydroxide (10 m l), sodium borohydride
solution (0.19 g of NaBH4 in 10 ml of 3M KOH)', and saturated salt solution
(10 m l).
It w as noted that cy clic alkene 3^took much longer tim e to react with
m ercuric acetate than 2.
This was indicated by the much longer tim e for the
disappearing of "the yellow color, which was from m ercuric acetate in aqueous
solution.
D istillation afforded a viscou s c o lo r le ss liquid with boiling point
140-1430C at 19-20 mm Hg.
Infrared* - 3400(8), 2950(8), 2900(8), 1470, 1450, 1440, 1380(8),
1368(8), 1325, 1290, 1270, 1255, 1235, 1210, 1177,
1150(8), 1120, 1110, 1080(8), 1055(8), 988(8), 971(8),
960, 949, 894, 846, 816, 793, and 741 cm"1
glc data - see table 20 and figure 42
The resulting alcohol mixture shows a broad unsym m etrical peak
(figure 42).
The glc analysis of the ratio of exo alcohol 33^ and endo alcohol
3 4 , by the method of triangulation, shows (30-40):(60-70).
JONE'8 OXIDATION OF.THE C IS -7 ,7, 9, 9-TETRAMETHYL-8-OXABICYCLO
[4. 3. 0]NONAN-3-OL8, (33) AND (34)
The usual procedure was carried out with the following quantities of
reactants: alcohol mixture of 33 and 34, (0.0025 m ole, 0 .45 g), acetone (3 m l),
Jone’s reagent (1.5 m l).
* (S = strong peak)
-6 2 The reaction mixture was extracted with methylene chloride, and the
extracts w ere washed with d istilled w ater, dried over m agnesium sulfate, and
then concentrated.
The infrared spectroscopy of the crude product shows a strong ketone
functionality, and also shows the lo ss of hydroxyl functionality.
The glc
analysis shows a sharp single peak for the crude ketone, and also shows the
disappearance of the alcohol peaks.
The y ield of this oxidation was 100% as
analyzed by glc.
glc data - see table 20 and figure 42
-6 3 -
Table 20: The R elative Retention Tim e of Compounds in
System 3.
Compound
£L h
Retention tim e '
(m in .)
a.
o)
J
3
54
4 .8
31 .2
C
&
33/34
f e x o /e ndo)
5 2 .8 /5 4 .7
The average of three injections.
b. Data obtained from Aerograph Autoprep Model A-700 gas
chromatography, with carbowax 20M column at 170°C,
and with flow rate HO m l/m in .
Figure 42: The Observation From the glc A nalysis of Compounds
in Table 20.
P A R T III
PREPARATION OF CIS-8-PHENYL-8-AZABICYCLO [4 .3 . 0] NON-3-ENE61, (37)
13
N-phenyl-1", 2 , 3 , 6-tetrahydrophthalimide , (53), (11. 35 g, 0. 05 mole)
w as refluxed 36 ,hours with LAH (7.6 g, 0 .2 m ole) -in 200 ml of anhydrous
ether., After the reaction mixture was worked up in the usual way for LAH
reduction, the solvent was stripped by the rotary evaporator.
product was slightly yellow solid.
The crude
R ecrystallization from E tO H -^ O afforded
6 .7 g (67.3% yield) of the white solid product 37_.
mp = 47 -48°C (Literature61; mp = 48°C)
PREPARATION OF CIS,-2-METHYL-;2-PHENYL-3a, 4, 7 ,7 a -T ETRAHYDROISOINDOLINIUM IODIDE, (42)
C is-8-p h en yl-8-azab icyclo [4.3. 0]n on -3-en e, (37), (I. 99 g, 0. 01 mole)
w as refluxed 12 hours with e x ce ss CHgI in approximately 50 ml of CHgNOg.
The solvent was stripped by rotary evaporation and left the crude product, the
green ish yellow gum.
R ecrystallization from EtOH-EtgO afforded the solid
salt 42.
PREPARATION OF CIS-N-M ETHYL-N-PHENYL-HEXAHYDROISOINDOLINIUM
IODIDE , (46)
13
C is-8-p h en yl-8-azab icyclo [4. 3. 0]nonane , (45), (2. 01 g, 0. 01 m ole)
w as refluxed 12 hours with e x c e ss CH3I in approximately 50 ml of CH3NOg.
The solvent was stripped by rotary evaporation, and left the crude product, the
yellow ish brown gum.
R ecrystallization from EtOH-Et3O afforded the solid
sa lt 46, with m elting point 215-216°C .
(Literature61; mp = 217°C).
PREPARATION OF CIS-2-M ETHYL-2-PROPYL-3a, 4 ,7 , 7 a-TETRAHYDROISOINDOLINIUM IODIDE62, (43)
13
C is- 8 -propyl- 8 -a z abicyd o [4. 3. 0]non-3-ene , (38), (I. 65 g, 0. 01 m ole)
w as dissolved in ether.
To th is, was slowly added 1 . 5 m l of methyl iodide.
slightly yellow solid was form ed quantitatively.
A
R ecrystallization from ethanol-
-6 5 ether gave the methiodide as c o lo rless c ry sta ls, mp 183-185°C .
(Literature62:
mp = 173-175°C ).
PREPARATION OF C IS -1,1 , 3 , 3-TETRADEUTERO-2-M ETHYL-2-PROPYL-3a,
4 ,7 , 7a-TETRAHYDROISOINDOLINIUM IODIDE, (44)
Iq
C is-7 , 7, 9, 9-tetradeutero-8-prdpyl-8-azabicyclo [4 .3 . 0]non-3-ene ,
(39), (I. 69 g, 0. 01 m ole), was dissolved in ether.
I . 5 m l of m ethyl iodide.
To this was slowly added
A slightly yellow solid was formed quantitatively.
R ecrystallization from ethanol-ether gave the methiodide as white cry sta ls,
mp 179. S - I S l0C.
APPENDIX
A P P E N D IX I
THE ANALYSIS OF GAS-LIQUID CHROMATOGRAPHY (GLC)
(1) The analysis of peak area:
The following methods w ere generally used for analyzing the peak
area:
(a) D isc integrator
(b) The method of triangulation
(c) The method of weighing the recording paper cut according to
the shape of the peak
When the D isc integrator is not available, the method of tr iangulation
and weighing are, usually, used sim ultaneously.
(2) The analysis of yield:
(a) An outer standard with the sam e number (or half the number)
of m oles as the reactant was carefully weighed, and then m ixed ,
with the to-be-analyzing product, and injected into the GLC
im m ediately.
By comparing the peak area of the outer standard
and the product, the yield can be found e a sily and consistently.
(b) Another method, som etim es used by som e ch em ists, is sim ply
comparing the peak area of the reactant and the product, to
calculate the yield of the reaction.
,APPENDIX II
THE COMMON COLUMNS USED FOR GLC ANALYSIS .
F & M Model 400 Biom edical Gas Chromatograph:
(1) 6 ft. 6 mm OD g la ss; 20% carbowax 20M on 30-60 m esh
F irebrick
(2) 6 ft. 6 mm OD g la ss; 5% SE 30 on 100-120 m esh Gas Chrom Z
Aerograph Autoprep Model A-700 Gas Chromatograph:
(1) 10 ft. 5 in. OD aluminum; 10% SE 30 on Chromosorb W
(2) 10 ft. 3 /8 in. OD aluminum; 20% carbowax 2OM on 30-60
m esh Firebrick
A P P E N D IX III
THE COMMONLY USED NAMES OF SOME OF THE HETEROCYCLIC COM­
POUNDS
Em pirical
formula
C8H12°
Structure
Commonly Used Names
(I) cis-8 -o x a b icy clo [4.3. 0]non3-ene
(2-a) c i s - 4 , 7 ,8 , 9-tetrahydrophthalan
(2-b) c is - A5 -tetrahydrophthalan
(3) c is-2 -o x a -3 a , 4 , 7 , 7 a -tetra hydroindane
C12H2 0 °
(1) c i s - 7 , 7 , 9, 9-tetram eth yl-8oxabicyclo [4. 3. 0] non-3-ene
(2) c i s - 1 , 1, 3 , 3-tetram eth yl- & tetrahydrophthalan
(3) c is - a,O', O'1, ft1, -tetram ethyl2-oxa-3a, 4, 7 , 7a-tetrahydroindane
c I4 h I 7N
(1) cis-8 -p h en y l-8 -a za b icy clo [ 4 . 3 . 0]n on-3-ene
(2) c is-2 -p h e n y l-3 a ,4 ,7 ,7 a tetrahydroisoindoline
A P P E N D IX IV
NMR SPECTRA
The nmr spectra of the following compounds w ere attached in this th e sis.
nmr
spectrum
number
structure
of
compound
solvent3
Co
i
2
»
4
*
B
17
‘
18 C$Q^' A
B
13
14
A
»
B
CDO
’
8
*
CC4
•
I"
a.
11
*
B
12
5 CO
6
solven t3
CO-O a
Cq S a
CCN
"cw
COq chic"
160 5 — , a
B
.
structure
of
compound
10
Co
3
nmr
spectrum
number
¥
I5
A
B
a
Jf3fp
Solvent A: deuter©chloroform
Solvent B: a mixture of de ute roc hi or of orm and deuterotrifluoroacetic acid, with a 50:50 ratio.
B
in solvent A
s.(,ns
in solvent A
I
in solvent B
in solvent A
in solvent B
in solvent A
S
IuVvv
in solvent A
jri S o lv e n t A
TMS
-C ^ c ti 2CH3
in solvent A
|'* ^« W A < w AVSav*-N*,,w * ^ * ,A'
-CH2CH2CH3
In Solvent B
In S olvent A
^ J J k HsCH2CH,
in solvent 3
/.os S
I
I
I
5. W
S
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:
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