INTRODUCTION
The relation between conformation and stability and
reactivity of alicyclic compounds was first established by
Barton1 in 1950.
Since then the subject has been well
2 7
8
developed and several reviews,” books
14
and a large
number of publications have come in this field.
The application of conformational analysis to
cyclohexane and its derivatives has been extensively studied.
Cyclohexane exists in the most stable chair form (T) 15 ' 16
whose stability is due to minimum energy.
In this form all
carbon-hydrogen angles are tetrahedral and the dihedral
angles are
1-3)
er.
are
60° and the H-H interactionsx'
2.5A°.
In this type of chair conformation,
the adjacent C-H bonds are staggered.
studies
18—► 21
”
(other than
X-Ray and I.R.
show that cyclohexane and its derivatives
prefer the chair conformation.
2
The chair form of cyclohexane can flip into an
45
_ i,
alternate chair form, at room temperature (10 -10
times sec
> «•
Such a flip, as shown in II, converts all the axial bonds
into equatorial bonds and vice versa.
For cyclohexane,
this
H
i
ring reversal does not result in a new isomer.
But in the
case of mono substituted cyclohexanes this reversal produces
another isomer.
Usually conformations with equatorial
groups are energetically favourable.
Similarly a poly-
substituted cyclohexane system is likely to have the
substituents of large steric requirements in the equatorial
positions.
The reason for this is that the axial substituent
increases the energy of the molecule through non-bonded
steric interactions with the axial hydrogen atoms or other
groups placed axially on the same side of the molecule.
This effect is known as 1,3-diaxial interaction.
3
A mono substituted cyclohexane exists as an
equilibrium mixrture of the two conformers with the equatorial
one in predominance in the equilibrium.
The negative free
energy change associated with the above equilibrium is the
conformational free energy of the substituent.
knowledge of the equilibrium constant (K)
From a
this energy is
calculated with the help of equation (i).
AG° = -RT In K
(i)
The conformational free energies of various
substituents have been determined by several workers 2 2 ~ 2'3-' .
These values provide information regarding the size of
groups.
Studies of the conformational equilibria by
Manoharan and Eli el 2S
of l-phenyl-3,3, t~5- trimethyl cyclo-
hexane by low terrperatnre 13 C N.M.R. spectroscopy indicate
that the 1,3-diaxial interaction of phenyl and methyl
groups to be 3.5 + 0.1 k cal.molT^
The gauche interaction
of methyl substituents in trans-1,2_dimethyl-cyclohexane
—1
is measured as 0.74 kcal .mol.
by making use of the same
technique of the conformational equilibrium of r-l-phenylt-3 ,C-4-dimethyl-cyclohexane .
Larger groups are more
likely to occupy equatorial positions and hence the
equilibrium will be shifted accordingly.
4
Recent studies indicate that a bulky group, when
substituted in the cyclohexane ring, restricts the ring to
26
a single chair conformation. Winstein and Holness
have
shown that a t«*t-butyl group largely prefers an equatorial
orientation.
The energy difference between equatorial and
-1
axial tert-butyl group is found to be 5.4-5.8 kcal .mol.
which is nearly equal to the energy difference between chair
and boat forms of cyclohexane.
Hence it is presumed that a
tert-butyl group or any bulky group in a six merrfoered ring
generally anchers it in a single chair form without ring
inversion.
This conclusion has led to the preparation of
conformationaly
homogeneous epimeric cyclohexane derivatives.
Accordingly^the reduction of 4-tert-butylcyclohexanone
afforded cis- and trans-4-tert-butylcyclohexanol s
26
Assuming the equatorial orientation of the tert-butyl group
in the chair conformation of the ring, the cis- and the
trans- isomers are represented by structures III and IV
respectively.
III
Studies on cis- and trans- isomers of
IV
6
The above equation is made use of in calculating the
free energy of the hydroxyl group 31
from the rates of
acetylation of cyclohexanol, and those of axial 4~tert~
butyl cyclohexanol and equatorial 4-tert-butyl cyclohexanol
with acetic anhydride in pyridine at 25°C.
In cyclohexanone system it is suggested
3 2- 34
that
as a result of trigonal geometry of the carbonyl carbon, an
equatorial substituent in the^>6 - or 2-position is nearly
eclipsed with carbonyl oxygen.
For any kind of alkyl group
in equatorial position next to a ketone function this
eclipsing would lead to an interaction energy term "2-alkyl
ketone effect" as presented in structure (VII) .
This
effect is significant when the group is bulkier than methyl
O C
group
.
2-alkyl ketone
effect
~R
VII
7
The cyclohexane rings in trans-decalin and other
fused ring systems present in steroids and triterpenoids are
restricted to a single chair conformation.
In trans-
decalin (VIII) each ring is attached to the other ring by
means of equatorial bonds.
Geometrically it will be
impossible to fuse a six membered ring to a chair cyclohexane
by means of two adjacent axial bonds.
not possible in this form.
Hence ring flip is
However, ring flip is possible
in cis-decalin (IX) where one ring is attached to the other
ring by means of one equatorial and one axial bond.
A
substituent in cis-decalin can assume either an equatorial
H
H
VIII
or an axial conformation.
IX
For example, cis-decalol can
exist in the following forms (X and XI) .
It should be
observed that the ring flip does not affect the cis
orientation of the hydroxyl group with respect to the
ring junction hydrogen atoms.
On the other hand, a substituent in trans-decal in occupies
a unique position, either axial or equatorial.
Trans-2-
decalols exist in two rigid forms (XII and XIII) .
H
OH
H
OH
H
XIII
Electron diffraction study shows that even in the
ideal chair form of cyslohexane, the theoretical values of
109.5° and 60° for endocyclic valency angles (
torsional angles
{jp 5
it)
and
36
respectively are not maintained(xiv)
The
and ^ values obtained from various experiments and
calculations differ considerably from theoretical values.
In Table I are presented the values of (p obtained for
cyclohexane and its derivatives.
XIV
The V value calculated from electron diffraction method
for cyclohexane by Davis and Hassel is 111.55° + 0.15 and
that calculated by Buys and Geise
is 111.05
+ 0.1-0.5.
These values, although agree each other very well, differ
fro'm the theoretical value of 109.5°.
It is generally recognized that the eclipsing
interactions in chair form are diminished in the boat
forms or twist boat forms.
shown in structure XV
The boat form of cyclohexane
is destabilised by the presence of
two eclipsed ethane type interactions.
interaction between the two flagpole
The non-bonded
hydrogen atoms of
Table - I
Method
Compound
\p
(°)
X-ray analysis
Cyclohexane
derivatives
(mainly l-,l,l~,
1,2- and 1,4sub stitut ed
53.2 - 57 .6
Force field
calculations
Cyclohexane
55.2 - 56.1
R_Value method
Cyclohexane
58 .0
Electron
diffraction
method
Cyc lohexane
54.5, 55.9
10
the boat will also render this form unstable.
It has been
suggested that the boat form, unlike the chair, is flexible
in that it can exist in an entire spectrum of conformations
Recent studies show the existance of different distorted
twisted conformations, of which the twist boat conformation
(XVI) commands the position of lower energy due to the
lower value of torsional strain(Et) .
Several studies indicate that either the boat or
the twist-boat or the twist-chair conformation exists in
various cyclic compounds under different conditions.
The
17
11
cyclohexane ring in 1,4-bridged cyclohexanes such as
bicyclo
[2.2. ]j
octane 37 ” 39
tion.
heptane (XVII)
and bicyclo
|2.2.2)
(XVIII) is forced to take up a boat conforma­
The geometry of fused polycyclic systems in
trans-syn-trans-perhydrophenanthrene (XIX)
and in
trans-anti-trans-perhydroanthracene4g (XX) forces the
central ring to adopt a boat conformation.
XIX
XX
12
Certain molecules having two or more atoms in a six
membered ring with hybridization other than sp 3 are found
to exist in twist boat form4 1 .
Cyclohexane-1,4-dione
exists in a twist boat form (XX.I) with carbonyl groups
inclined at an angle of 180°.
This is known from dipole
moment and spectral studies4 2-46 .
Such molecules are
considered to have an inherent preference for the boat
family.
In tran s-1,3-di-t-butylcyclohexane, the 1,3-
diaxial interaction of the bulky tertiary butyl groups is
relieved in the twist boat form (XXII).
XXII
13
Twist-boat forms and boat forms of six membered
alicyclic rings as well as other cyclic systems are greatly
stabilised through hydrogen bonding.
The twist-boat
conformation of cis-l,4-di-t-butyl-cis-2,5-dihydro xycyclohexane is stabilised by intramolecular hydrogen bonding4 7
as shown in (XXIII) .
H
48
Kwart
has demonstrated the relative greater
flexibility of the boat form compared to the chair form.
Precisely the same P.M.R.
spectrum is observed below
0
-80 C as obtained at room temperature
for the 3,5-
diketone of 1,1-dimethyl-4 ,4-dibenzyl cyclohexane (which
exists in the twist-boat form)
suggesting that low
temperatures do not freeze out any important modes or
seriously interfere with the flexibility.
14
Lambert et al 4Q have suggested a diagnostic method
for finding out the various ring deformations through P.M.R.
studies.
This method is known as the R value analysis, where
R=J transAJcis.
On the basis of R values the following
generalisation, as given in Table II, has been made regarding
the ring shape.
Table II
R values and conformations
R=J transAl cis
Con forma tion
e
Cyclohexane-like chair
^60°
2.5
Puckered chair
< 60°
1.8
Flattened or flexible chair
>60°
1.9 - 2.2
The above analysis employing R values, mainly leads to six
kinds of ring systems as shown in structures (XXlVa XXIVf) .
The above mentioned R value analysis gives only
approximate results.
However a more accurate R value
analysis employing pentamethylene ring systems has been
suggested by Lambert and Keske 50
15
Twist boat
9= 90°
Twist boat
_ = 30 o , 150 o
©
Flattened chair
Puckered chair
or
the sulphur distortion
XXIV
16
In the pen tame thylene rings,
(CH^)_X , P.M.R. spectral
<L b
data of the appropriately deuterated species (XXV and XXVI)
have yielded two different R values, one based on the
hydrogen atoms in C©4 and
and other based on those in
C 6 and C"2l .
The average of the two R values is taken as a measure of the
conformational description of the rings.
The R value
analysis of thiane and 1,1-dibromotellurane is presented
in Table III.
Table III
R-value analysis of (CH2>gX ring.
Compound
Thiane
Rotj^
2.61
1,l-Dibromo~
tellurane
1.5
Rp5
Conformation
2.58
Puckered chair
3.6
Flattened chair
17
The Ro6
p and
Rpj"^ values for thiane are almost equal.
They
are greater than that for the normal chair, viz. 1.9-2.2,
This indicates that (p eShas diminished resulting in the
puckering of the ring.
In 1,1-dibromotellurane the R
value is less than 1.8.
This indicates a widening of tp €£•
(flattenings of the chair form).
R value greater than about
2.5 indicates closing of lp£6and a puckering of the ring
so that the ring is partly flattened and partly puckered
from the chair form.
In conclusion four conformational
classes are delineated as given below.
1.
If both R©CjS are l.S-2.2, the ring is rather close
to the perfect chair.
2.
If both quantities are considerably larger than 2.2,
the ring is substantially puckered.
3.
If R
is small, but R^tf large (or vice versa)
part of the ring is flattened and part is puckered.
4.
If both R values are small, the molecule is either
doubly flattened or in a flexible family.
Sven
though individual twist-forms can have R values
greater than 2.0, the averaging of dihedral angles
through pseudo-rotation will always bring both
R
and
Rf
to 1 ess than 2.0.
18
The stereochemistry of saturated six membered
heterocycles has many features in common with the stereo­
chemistry of cyclohexane system.
Saturated six membered
heterocyclic compounds prefer chair conformation with
equatorial substituents.
.
physical measurements.
This has been proved by many
81 5 2
It is found that piperidines'* '
1,2-diazanes and 1,3-diazanes
nc
piperazines
~
Q o
53-69
, 1,3,5-triazanes
CM
and 1,2,4,5-tetrazanes
~
QQ
70-75
,
exist in
chair-conformation.
X-ray analysis of N,N'-dichloropiperazme
90
shows
that the two chlorine atoms are equatorial in the chair
form.
O 1
2,4 ,6-Trimethyl-l, 3, 5-triazacyclohexane''
exists
in the chair form with all the three methyl groups in the
equatorial position (XXVII).
I Me
H
H p|
XXVII
19
dicarboxylic acid (XXVIII)
is more stable than the
cis-3,6-diacid (XXIX).
coon
H
hooc_
H
o
" —COOH
:OOH
H
H
XXIX
XXVIII
9 3 94
It is observed
'
pseudo-tropine<XXX)
that the N_acyl derivatives of norare easily converted to the respective
o-acyl derivatives (XXXI),
equally facile.
the reverse migration is also
But the acyl derivatives of nor-tropine
with axial OH failed to undergo such type of migration.
This shows that the C-3 hydroxyl and the nitrogen bridge
are cis- to each other in nor-pseudo-tropine while in
nor-tropine the hydroxyl group and the nitrogen bridge
are trans to each other.
This migration involves an
intermediate in which the nitrogen and the oxygen are
bridged by a carbon atom as shown below.
The formation
20
of this intermediate is easier in ^XXX> than in nor-tropine.
*2 CO
3.
."'if*1 1
h2nTl'x
'
V
u
\
OCOR
H
XXX
XXXI
The lupine alkaloids can exist in the following
fused-chair ganformation (XXXXI and XXXIII) resembling
trans- and cis- decalins respectively|
H
H
XXXII
In these the lone pair electrons on the nitrogen take
the place of one of the bridge-hydrogen atoms in decalin.
The stable conformation of 9-az-adecalin resembles that
of stable trans-decalixu
Such type of conformations are
found in lupine alkaloids, .->o -isosparteine and
^ -i93sparteine .
The following structures are assigned
to lupinine (XXXIV)
and epilupinine (XXXV) on the basis of
spectral and other chemical
9 5-98
studies
XXXIV
XXXV
The introduction of heteroatoms into a carbocycl ic
ring produces a change in the conformational characteristic
of the ring.
The presence of heteroatom in the ring alters
the torsional arrangements of the atoms and affects the
99-106
rotational barriers of various bonds
.
Energy
barrier to ring reversal and boat chair energy differences
are influenced by heteroatoms.
It is found that the force
constants for bond angle deformation of heteroatom vary
from those of carbon atoms
.
Also in some of the
heterocycles, it is found that the heteroatom induces
a strong dipolar effect with respect to polar substituents,
119
particularly those on the adjacent carbon atoms
1 1 Q
.
22
As a result, it tends to drive the substituents into axial
’position.
This effect is known as anomeric effect.
the simplest examples is 2-alkoxytetrahydropyran
120
One of
, for
which two conformations (XXXVI) and (XXXVII) are possible.
But the one with axial alkoxy group (XXXVII) predominates
the equilibrium with 60-90%.
XXXVII
XXXVI
Intramolecular hydrogen bonding between hydroxyl
groups and heteroatoms can influence the preferred
conformation.
In 5-hydroxy-1,3-dioxane due to hydrogen
bonding, conformation with axial hydroxyl group is
favoured (XXXVIII) .
6
-
H
XXXVIII
23
The boat forms in heterocyclic systems are stabilised by
hydrogen bonding 121-122 .
The compound 1,2,2,6 ,6-penta-
methyl-4-phenyl-4-piperidinol
123
, is found to exist xn
the boat form (XXXIX) through hydrogen bonding.
Intramolecular hydrogen bonding is observed in 3-hydro xypiperidines
1 24
enabling them to prefer chair forms with
hydroxyl group in the axial position.
*2
/
0
‘
-
-h'
xxxx
24
One of the most important issues in the study of the
conformations of piperidines has been the establishment of
the orientation of the lone pair of electrons on nitrogen
atom.
Aroney and Lefevre 125 measured the molecular
polarizabilities of piperidine, N-methyl piperidine and
morpholine in benzene solution and have shown that the
rings are in the chair form and that the "volume" requirement
y
ares lone pair
methyl group
hydrogen atom. This
paper has initiated a considerable amount of studies in
various schools.
Dipole moment results
'
have led
to the conclusion that the lone pair possesses a smaller
steric requirement than the hydrogen atom.
The dipole
moment studies of substituted piperidines by Katritzky
et al show that the N-H prefers the equatorial position in
the gas phase and in non interacting solvents and the energy
difference between equatorial and axial N-H is found to be
,128
approximately 1.68 kJ mol”"
.
Infrared studies in
the gas phase 129
studies
and in solution 130
and the microwave
are in agreement with this preference.
The
orientation of N-alkyl substituents in piperidines,
determined by dipole moment and IR measurements
confirms
that increase in the bulk of the alkyl group increases the
1 *30
proportion of axial N-lone pair
1 Q
'
.
25
4-Piperidinols are formed by the reduction of
4-piperidones employing various reducing agents like NaBH^,
LiBH4, Pt/H2, Al( iso-Pro) 3 and Li/NH3 - MeOH.
The
reductions are mostly stereoselective in favour of a
particular isomer of piperidinol.
axial piperidinol is favoured.
Padma 134 ' 135
In a few cases the
Balasubramanian and
studied the stereochemistry of reduction of
various substituted 4-piperidones and showed maximum
yields of the 4-piperidinol s with OH- equatorial in the
catalytic reduction in acid medium and in the reduction
with LiAlH^ and Na/n-butanol whereas the axial alcohols in
the catalytic reduction in neutral medium.
In the case of
1,2,2-.trimethyl-6-phenyl-4~piperidone the axial alcohol was
exclusively the product irrespective of the medium.
In the
Meerwin-Pondorf-Verley reduction of substituted 4-piperidones
only the axial epimer predominates due to steric factor of
the attacking bulky reducing agent.
*1
Haller and Ziriakus
i
studied the
H NMR spectra
of 3-methyl-cis-2,6-diphenyl-4-piperidone oxime and
1,3-dime thyl-ci s-2,6-diphenyl -4-piperidone oxime in
pyridine and found that the oxime hydroxyl is anti- to
0^-alkyl substituents.
The PMR spectra of 3,5-dime thyl-
ci s-2 ,6-diphenyl -4-piperidone oxime and 1,3,5-tr ime thylci s-2,6-diphenyi-4-piperidone oxime show ring distortion
26
in the two molecules.
For l,3,5-trimethyi-.cis-2,6-
diphenyl-4-piperidone oxime a twist boat conformation has
been suggested by them.
The PMR studies on compounds
(XXXXIa - XXXXld) by Haller and 2iriakus 117
reveal that
the chemical shifts of the equatorial and axial protons
of the syn methylene group differ due to the magnetic
anisotropy of the hydroxyimino group.
A rapidly inverting
chair conformation was assigned to (XXXXIb) and (XXXXIc)
XXXXI
28
show that in all the 2e, 3e- disubstituted cyclohexanone
oximes, the hydroxyl group attached to the nitrogen is
anti- to the Csubstituent.
The stereochemistry of the
oximes of 2-phenyl-and 2,3-diphenyl-1-tetral ones is also
reported
141
.
In these case a different orientation of the
hydroxyl group is observed.
PMR spectra of (XXXXIIb)
(a)
X
Rr Ph?
Rr Ph;
r2= H;
x=o
r2= H?
X=NOH
(c)
V Ph;
r2= H; X=FOAc
(d)
Rr:R2= Ph;
(b)
X==0
(e) Ri=:R2= Ph;
Xs-NOH
(f)
Xs=N0Ac
ri=:R2= Ph;
XXXXII
show that the Cg-proton is shielded and C
2
proton is
deshielded corrpared to that found in (XXXXII a) .
This may
be due to the orientation of hydroxyl group syn- to the
C ~ substituent arising due to severe steric interaction
2
between the oximino function and the Cg hydrogen which
prevents the orientation of the hydroxyl anti- to C2
substituent.
The coupling constant of the C2 hydrogen
29
with C3 hydrogen, points that in (XXXXIIb)
the hydroxyl
group of the oxime is oriented syn- to the C2~phenyl group
which assumes the pseudo axial orientation.
Similar
orientation of groups is found in the case of (XXXXlIe)
also.
However, here the ring is distorted due to the
introduction of the additional C^-phenvl group.
The
configuration of several oximes and of their methyl ethers
including those of cyclohexanone was studied by Karabatsos
and Hsi 14 2
in the compounds of the type (XXXXIII) with
1
the help of
H NhR spectra.
Z
N
ij
y
B
/
/
R
A
Z = OH or OMe
Rx
XXXXIII
Generally it is found that region A is found ae shielded
compared to B.
The radicals formed^
in the oxidation of
oximes by lead tetraacetate (LTA) or ceric ammonium
nitrate help to establish the configuration of the
oximes.
Generally in these cases the epr detects mainly
nitroxide and iminoxy radicals.
Oxidation of benzaldoxime
30
,
.
.
by ceric ammonium nitrate
Thomas
148
14 8
produces the lmmoxy radical .
suggested that epr spectra are useful in detect­
ing the syn- and anti- isomers of oximes.
The LTA oxidation
of aliphatic and alicyclic ketoximes produces gem-nitroso
acetates
149
(eqn.l).
The oxidation of
sterically hindered
ketoximes results in C-C bond clevage rather than the
formation of nitrosoacetate (eqn.2).
In the case of
2,2,6 ,6-tetra substituted cyclohexanone oximes, the C-C
bond clevage occurs.
HO
N
IT A
31
The following emprical rules have been suggested in
respect of the iminoxy radical.
1)
The iminoxy radical has a long range interaction
which is transmitted through the sigma-bond system
o f mol ecul e.
2)
y) f) p / 2
The interaction of the radical with the components
of molecules lying cis relative to oxygen is
essentially stronger than those lying trans.
3)
The interaction of the radical is most effective
when the H-(C) -F-C fragment is planar.
su r\s
Conformationally homogeneous epimeric cyclohexane and
heterocyclic derivatives show different reactivities.
The
esterification of an equatorial alcohol proceeds faster
than its axial ©pimer.
The solvolysis of an axial tosylate
is faster than its equatorial isomer.
An axial alcohol is
is oxidised by chromic acid faster than its equatorial
isomer^'^'*^^ .
The difference in the rates of oxidation
of epimeric alcohols has been rationalised on conforma­
tional grounds.
The explanation offered for the fast
reactivity of axial carbocyclic and heterocyclic alcohols
in the oxidation is that in the axial alcohols the strain
in the ground state is relieved in the transition state.
0
32
The kinetics of Vanadium(V) oxidation of a number of
epimeric pairs of 4-piperidinol s
153
show that axial
alcohols react faster than the corresponding equatorial ones.
The kinetics of chromic acid oxidation of cyclohexanone
and of 2,2,6 ,6-tetradeutrocyclohexanone have been studied* in
detail by Best, Littler and Waters
effect (kH/kD)
154
.
The Kinetic lsotooe
and solvent isotope effect (MI^O/kH^O) have
been measured and the possible mechanisms of oxidation of
cyclic ketones by chromic acid have been suggested.
The
above studies show that the oxidation of ketones follows
enolisation and the rate determining step involves both the
oxidant and the substrate.
Agatha Riehl
155
The study of Jan Roce* k and
with isobutyrophenone, cyclohexanone and
2-chlorocyclohexanone gives additional support to the
mechanism of oxidation by chromic acid.
The kinetics and
mechanism of chromic acid oxidation of aliphatic ketones
have been studied in detail by Tandon, Banerji and Bokore 156
Baliah
157
studied the chromic acid oxidation of some
substituted epimeric 4-piperidinol s and shows that the
reactivity depends on the steric environment of the hydroxyl
group and hence the conformation of the alcohols.
He also
studied this oxidation by varying the hetero atom 158
and
measured the influence of the hetero atom on reactivity.
33
The oxidation of oximes by ceric ions leading
to the
formation of parent carbonyl compounds has been observed by
Bird and Diaper
159
and a free radical mechanism in this
oxidation has been suggested by them.
Following this study,
several oxidising agents have been used by various workers
for the conversion of oximes to their respective ketones.
The reactions were very fast in many cases to follow them
kmetically.
.
160,161
However, Santappa ana co-workers
have
followed the kinetics of oxidative hydrolysis of some oximes
by metal ions.
Ganapathy and Vijayan 16 2
have studied the
kinetics of oxidation of cyclohexanone oxime in perchloric
acid by N-chloro-3-methyl-2,6-diphenyl_4-piperidone and
proposed an ionic mechanism.
163
Shan mug an a than and co-workers '
have studied the kinetics of oxidation of cyclohexanoneoxime
by chloramine-T.
The reaction was-zero order in oxidant
and first order in substrate.
A suitable mechanism has been
proposed by them.
Bicyclic sy stem
Among the bicyclic bridged hydrocarbons one which
deserves mention is the bicyclo
|3.3.1j nonane.
The model
of this hydrocarbon shows that there is transannular
interaction between the axial hydrogens at
(XXXXIV) .
and
34
In most cases the chair-chair conformation with slight
ring flattening is favoured^^
in twin-chair
conformation the actual distance between the C3 and C7
carbon is 3.06A° while the ideal value is 2.52A°.
The
flattening occurs in order to minimize the transannular
interaction between the endo-axial hydrogen atoms at
and
positions.
If these hydrogens are replaced by
bulky groups one of the rings may assume a boat form.
Bicyclo
|3.3.l| nonane system shows some interesting
conformational features.
Generally three groups of
conformations are considered^8 (XXXXV) .
(i)
The rigid double chair conformation (cc) .
(ii)
The rigid chair-boat (or vice versa) con formation
(cb, be).
(iii) The flexible double conformation (t-bb-bb) .
35
The eclipsed double boat conformation (bb)
appears to be a
intermediate state between the two double twist-boat
conformations (t-bb) .
In the boat-chair conformation also
unfavourable interaction occurs between H ,,^/H^
and H ^
and between H_* and one of the H„ atoms.
As a result of
3p
S
which as in chair-chair (cc) conformation, the ring
flattening occurs in boat-chair (be or cb)
form also.
It
is found that in bicyclic system, the energy difference
between the cc and the be conformations is 10.5 KJ mol -1 ,
whereas that between be and t-bb is computed to be
22.6 KJ mol’1.
Substituents at 3,7 positions have a strong influence
on the conformational preferences.
3^ or the 7^
A substituent at the
position stabilizes the cc form.
But a 3°^
or 7 ^ group forces the substituted wing into the boat
conformation when substituents are present on both the
3^ and 7®^ positions, cc is strongly disfavoured whereas
the population of the other conformations depends on the
size of substituents.
With two bulky groups such as those
in compound (XXXXVI), the t-bb predominates.
The presence
of one small and one bulky group at positions 3 and 7 causes
an equilibrium among the cb or be forms with the predominance
P
t-bb
36
38
of cb or be conformations (XXXXVII
and
XXXXVIII).
the 3 K' and .7°^ substituents are small (XXXXIX
both cb and be can contribute.
when the 3
and
When
XXXXX)
A special situation arises
and l&C positions are substituted with small
and identical group; the be and cb become isomeric
(XXXXXI).
The 3,7-dicarboxylic acid and its ester of the
bicyclo ("3.3.l] nonane system exist predominantly in the
rapidly interconverting cb and be v^iich is reflected in
the averaged
1
H and
13
C signals for the exohanging nucl®x
in the two wings of the system.
The interconversion is
fast with respect to the NMR time scale, therefore no
activation energy for this interconversion could be
determined.
Peters and co-workers
1 AA
following three 3-7-dimethyl bicyclo
(XXXXXI) , (XXXXXII)
and (XXXXXIII)
prepared the
j
3 *3.1J nonanes,
and established the
conformations through 1 H and 13 C NMR studies.
XXXXXII
XXXXXIII
39
The IR spectra of the azabicyclo
f3.3.1jnonan_9-ones
in the region of C-H stretching vibrations contain additional
bands that are shifted to low frequency region relative to
169
the normal C-H stretching vibrations.
These bands,
otherwise known as Bohlmann band
170
,
arise because of
interaction of the lone pair electron of nitrogen with an
171 172
anticoplanar C-H bonds in piperidine ring.
'
possible
This is
in the conformer in which the lone pair electron
should be oriented endo to the ring.
0
Crystals of different
0
xxxxxv
forms of 2,4-diphenyl-3-azabicyclo j3.3.li nonan-9-one
have been obtained by recrystallisation in non-polar
and polar solvents‘P^~’‘^~'
The IR spectrum of (XXXXXIV)
-l169
shows Bohlmann bands in the region 2700-2840 cm” .
40
3~Methy 1-3-azabi eye lo
3.3,1
tetraphenyl-3-azabicyclo
Bohlmann bands4-
'
nonan-9-one and 2,4,6,8-
|3.3.lj-
nonan-9-one also exhibit
in the region 2600-2800 cm”
.
This
confirm the following structures (XXXXXVI and XXXXXVII)
for the compounds.
0
0
XXXXXVII
3,7-Dimethyl-3,7~Diazabicyclo | 3.3. lj nonane forms
a monoperchlorate and this has a symmetrical structure
which shows a sharp singlet for methyl protons.
The
chemical shifts observed for thet^ -methylene protons in
bispidin
and N-methyl piperidine are similar.
supports that the latter exists in twin chair
This
41
conformation
177 (XXXXXVIII)
On the basis of the J
HCOH
XXXXXVIII
value, the conformation of 1,5-dinitro-3-methyl-3azabicyclo
|3.3.lj
nonane-7-endo-ol has been determined
to be (XXXXXIX) 178 .
XXXXXIX
42
The
J„„„ is found to exhibit a dependence on the
rlC.uri
dihedral angl e1^"" '
.
Large values of JhcoH trans
(Ca.l2Hz) have been reported for compounds in which the
-OH hydrogen is constrained by H-bonding to be anti- to
the carbinol hydrogen.
A similar value of
(Ca.l2Hz)
for the above mentioned compound suggests a transoid
arrangement ( © 2C180°) of H-C-OH bonds in accord with
the hydrogen bonded chair-chair conformation.
band width suggests diaxial coupling
of (XXXXXIX)
at
/
18 1
.
Larger half
In the spectrum
the half band width of 11 Hz for the multiplet
4.2 due to C
proton confirms its twin chair
conformation with carbinol proton at C q
endo to the
C7 proton.
Hartmann, Wermann, Grafe
18 2
and co-workers have
studied the iminoxy radicals formed from a series of bicycli
oximes by oxidising them with lead tetraacetate (LTA).
Besides aN (nitrogen h.f.s)
observed.
(hydrogen h.f.s) are also
The various proton interaction with the iminoxy
odd electron is based on the general conclusion that the
most effective coupling occurs via a planar<s~~-frame work,
cis- to the iminoxy oxygen.
bicyclo
|3.3.l|
The two®C -hydrogen atoms in
nonan-3-one oxime are equivalent, having
43
= 2.68 gauss, a result very close to cyclohexanone oxime
radical in which a "chair-chair" inversion occurs.
Hence it
is presumed that the cyclohexanone ring in the bicyclic oxime
undergoes "chair-boat" isomerisation at a higher frequency
as to result in an average splitting for theoL-hydrogen
atoms.
The splitting of about 4 gauss expected from
interaction with^-equatorial proton could not be observed
in many of the bicyclic coimpounds in which ring fusion
(1,5-fusion) existsCKf- to the iminoxy radical.
It is
suggested that the nearly 50% lowering of the equatorial
-proton h.f.s
is due to the substitution of a hydro­
carbon chain at the-carbon atom.
Ivan and Sahini
of the
Caldararu, Barbuleseu,
have produced iminoxy radicals of some
^-bridge head bicyclic oximes by oxidation with LTA.
All iminoxyradical s investigated have an
^(-bridgehead
proton in an equatorial position and the splitting of
1.90 gauss is observed.
Besides iminoxy radicals, nitroxide
radicals are also produced in some of the bicyclic oximes.
The oximes of bicyclo
j3.3.f) nonane system, bicyclo |_3.2.lj
octane system and bicyclo f4.2.l] nonane system produce
mainly nitroxide radicals during LTA oxidation
184
According to the epr, the radicals are mainly divided
into three groups.
Of which, type 1 group of nitroxide
44
radicals having
aN -
13 gauss are suggested to be
formed through iminoxy radical.
The attack of an acetate
radical on it produces the gem-nitrosoacetate which
finally dimerizes to give this kind of nitroxide radical,
A survey of the literature reveals that no kinetic
study on the oxidation of 4-piperidones by chromic acid
has been so far reported.
Hence it was considered of
interest to prepare a series of substituted 4-piperidones
and carry out the kinetics of their oxidation by chromic
acid in order to study their conformations.
The earlier studies on oximes were mainly carried
out to gain informations about their geometrical isomers,
syn and anti forms.
These configurational features were
mainly studied through PMR spectra.
Alicyclic as well as
heterocyclic six merribered rings possessing the oxime
group also exist in syn and anti forms.
The groups
present in the neighbouring carbon atoms of the oxime
group force the oxime-OH group to lie in the anti( 1-3)
position which mainly arises from the A
strain.
In substituted 4-piperidone oximes such effects are
observed.
In 4-piperidone oximes when both sides of
the ring carbon atoms of the oxime group are substituted,
the ring distortion is observed.
confirmed through PMR studies.
This distortion is
But so far no kinetic study
has been made with heterocyclic oximes with a view to
establish the effect of substituents on ring distortion and
conformation.
Hence the author converted a number of
substituted 4—piperidones into the corresponding oximes and
carried out tlie kinetics of their oxidation with thallium (III)
acetate.
These oximes were also oxidised by leadjtetra-
acetate (LTA) and the generated radicals were studied through
their epr spectra.
also recorded.
The PMR spectra of these oximes were
All these studies were made to establish the
conformations of these oximes.
The author prepared a number of 2,4—diaryl-3-azabicyclo
,3*3»t.
nonan-9-one and converted them to the corresponding
oximes and the NMR spectra of these oximes were recorded to
study their ...conformations.