A MECHANISTIC STUDY OF COMPLEX BASE-PROMOTED
1,2-ELIMINATION REACTIONS
by
ALAN PAUL CROFT, B.S.
A DISSERTATION
IN
CHEMISTRY
Submitted to the Graduate Faculty
of Texas Tech University in
Partial Fulfillment of
the Requirements for
the Degree of
DOCTOR OF PHILOSOPHY
Approved
^-^
uecemoer, i^oj
7 -^
ACKNOWLEDGEMENTS
I wish to express my gratitude to my wife, Denise,
and to my family for their support and understanding during
the course of this research.
I would also like to acknowledge
the invaluable assistance of Professor Richard A. Bartsch.
Without his encouragement and guidance, this dissertation
would not have been written.
Acknowledgement is also made to the Donors of the
Petroleum Research Fund, administered by the American Chemical
Society, for support of this research.
11
CONTENTS
ACKNOWLEDGEMENTS
LIST OF TABLES
LIST OF FIGURES
I.
INTRODUCTION
Mechanisms of Base-Promoted 1,2-Eliminations Which
Form Alkenes
. . ..
Fundamental Mechanisms
Variable E2 Transition State Theory
Probes of Mechanism and Transition State Structure
..
Variation in Structure of Elimination Substrate
..
Variations in Base and Solvent
Kinetic Isotope Effects
Stereochemistry of E2 Elimination Reactions
Introduction
Anti vs. Syn Elimination
Orientation in E2 Elimination Reactions
Formulation of Research Plan
Complex Base-Induced Elimination - Background
Statement of Research Problem
II.
EXPERIMENTAL SECTION
Preparation of Substrates
trans-1,2-Dibromocycloalkanes
trans-1,2-Dibromocyclobutane
trans-1,2-Dibromocyclopentane
trans-1,2-Dibromocyclohexane
•• •
111
. . ..
trans-1,2-Dibromocycloheptane
30
trans-1,2-Dibromocvclooctane
30
trans-1,2-Dichlorocvcloalkanes
30
trans-1,2-Dichlorocyclopentane
30
trans-1,2-Dichlorocyclohexane
30
trans-1,2-Dichlorocycloheptane
31
trans-1,2-Dichlorocvclooctane
31
trans-1,2-Dichlorocyclododecane
31
trans-l-Bromo-2-chlorocycloalkanes
32
trans-l-Bromo-2-chlorocyclobutane
32
trans-l-Bromo-2-chlorocyclopentane
34
trans-l-Bromo-2-chlorocyclohexane
35
trans-l-Bromo-2-chlorocycloheptane
35
trans-l-Bromo-2-chlorocyclooctane
35
trans-l-Chloro-2-fluorocycloalkanes
36
trans-l-Chloro-2-fluorocyclopentane
36
trans-l-Chloro-2-fluorocyclohexane
36
trans-l-Chloro-2-fluorocycloheptane
36
trans-l-Halo-2-methoxycycloalkanes
37
trans-l-Chloro-2-methoxycyclopentane
37
trans-l-Bromo-2-methoxycyclohexane
37
trans-l-Chloro-2-methoxycyclohexane
38
trans-l-Fluoro-2-methoxycyclohexane
38
trans-l-Chloro-2-methoxycycloheptane
38
cis-1,2-Dichlorocycloalkanes
IV
....
39
cis-1,2-Dichlorocyclopentane
39
cis-1,2-Dichlorocvclohexane
40
cis-1,2-Dichlorocvcloheptane
40
cis-1,2-Dichlorocvclooctane
40
cis-1,2-Dichlorocvclododecane
40
ll,12-Dichloro-9,10-dihydro-9,10-ethanoanthracenes
, .
41
trans-11,12-Dichloro-9,lO-dihydro-9,10-ethanoanthracene
41
cis-11,12-Dichloro-9,lO-dihydro-9,10-ethanoanthracene
42
trans-2-Chloro-l-cyclohexvl Phenyl Sulfide and Sulfone.
42
trans-2-Chloro-l-cyclohexyl Phenyl Sulfide
42
trans-2-Chloro-l-cyclohexyl Phenyl Sulfone
42
Miscellaneous Elimination Substrates
43
trans-l-Chloro-2-tosyloxycyclohexane
trans-[(2-Chlorocyclohexyl)oxy]trimethylsilane
43
...
43
trans-2,3-Dichlorotetrahydropyran
44
(E)-l,2-Dichloro-l-methylcyclohexane
44
Preparation of Authentic Samples of Elimination Products.
1-Bromocycloalkenes
45
45
1-Bromocyclobutene
45
1-Bromocyclopentene
45
1-Bromocyclohexene
45
1-Bromocycloheptene
....
46
1-Bromocyclooctene
46
1-Chlorocycloalkenes
46
1-Chlorocyclobutene
46
V
1-Chlorocyclopentene
45
1-Chlorocyclohexene
47
1-Chlorocycloheptene
47
1-Chlorocyclooctene
47
(E)-l-Chlorocyclododecene
47
(Z)-l-Chlorocyclododecene
48
1-Methoxycycloalkenes
49
1-Methoxycyclopentene
49
1-Methoxycyclohexene
49
1-Methoxycycloheptene
49
3-Methoxycycloalkenes
50
3-Methoxycyclopentene
50
3-Methoxycyclohexene
51
3-Methoxycycloheptene
51
Cyclohexen-1-yl Phenyl Sulfides and Sulfone
51
1-Cyclohexen-l-yl Phenyl Sulfide
51
2-Cyclohexen-l-yl Phenyl Sulfide
52
1-Cyclohexen-l-yl Phenyl Sulfone
52
Miscellaneous Elimination Products
53
ll-Chloro-9,10-dihydro-9,10-ethenoanthracene
....
53
(1-Cyclohexen-l-yloxy)trimethylsilane
53
5-Chloro-3,4-dihydro-2H-pyran
53
Procedures for Elimination Reactions
54
Complex Base-Induced Eliminations
54
Preparation of Complex Base
VI
54
Standard Complex Base Elimination Procedure
Competitive Complex Base Elimination Procedure
....
54
...
55
Control Experiments
55
Eliminations Induced by Potassium t^-Butoxide in
_t^-Butanol
55
Preparation of t^-BuOK-t^-BuOH
56
Elimination Procedure for t^-BuOK-t^-BuOH
57
Control Experiments
57
Gas Chromatographic Analysis
III.
57
Compound Purity Determinations
58
Analysis of Elimination Reaction Mixtures
58
Molar Response Studies
59
RESULTS AND DISCUSSION
64
Synthesis of Elimination Substrates
64
Mechanistic Features of Complex Base-Induced
Elimination
66
Nature of the Complex Base
72
Effect of Ring Size Variation upon Competitive
Dehydrobromination and Dehydrochlorination Promoted
by Complex Base and by t^-BuOK-_t-BuOH
Competitive Syn and Anti Dehydrochlorination
Induced by Complex Base
Leaving Group and B-Activating Group Effects
81
87
....
97
x-Activating Group Effects
108
Elimination from Substrates with Non-halogen
6-Activating Groups
112
Vll
I^v
IV.
CONCLUSION
121
LIST OF REFERENCES
123
APPENDIX
128
Vlll
LIST OF TABLES
1.
Effect of Solvent and Crown Ether on Syn and Anti
Contributions for _t-BuOK-Promoted Eliminations
from 5-Decyl Tosylate
19
2.
Molar Response Values
60
3.
Elimination Reactions of trans-l-Bromo-2-chlorocyclohexane Induced by NaNH2-NaOCR-^R^R-^ in THF
at Room Temperature
73
Elimination Reactions of trans-l-Bromo-2-chlorocyclohexane Induced by NaNH2-NaAnion in THF at
Room Temperature
79
Syn Eliminations from trans-l-Bromo-2-chlorocycloalkanes Promoted by Base
83
Competitive B-Halogen Activated Syn and Anti Dehydrochlorination from ^ and 2_4, or ^ and l^. ^'^~
duced by NaNH2-NaO-_t-Bu in THF at 20.0°C
91
Competitive Syn and Anti Dehydrochlorination from
cis- or trans-1,2-Dichlorocyclododecane Induced
by NaNH2-NaO-_t-Bu in THF at Room Temperature, or
_t-BuOK-_t-BuOH at 50.0°C
95
Leaving Group Effects for Eliminations from trans1,2-Dihalocycloalkanes Promoted by NaNH2-NaO-_t-Bu
in THF at 20.0°C
101
B-Activating Group Effects for Eliminations from
trans-1,2-Dihalocycloalkanes Promoted by NaNH2Na0-_t-Bu in THF at 20.0°C
102
4.
5.
6.
7.
8.
9.
10.
11.
12.
Leaving Group and B-Activating Group Effects for
Syn-Exo Eliminations from 2,3-Dihalonorbornanes
Promoted by Sodium Pentoxide in Pentanol at 110°C
. . .
104
Dehydrohalogenations from Elimination Substrates
Containing Non-halogen B-Activating Groups, Induced by NaNH2-Na0-_t-Bu in THF
114
Dehydrohalogenations from Elimination Substrates
Containing Non-halogen B-Activating Groups, Induced
by t-BuOK-t-BuOH at 50.0°C
116
IX
LIST OF FIGURES
1.
Variable E2 Transition States
7
2.
More 0*Ferrall Potential Energy Surface for Elimination
Reactions
9
3.
Newman Projections of Selected Elimination Stereochemistries
16
4.
B-Halogen Activated Syn and Anti Dehydrochlorination . . .
89
5.
Competitive Syn and Anti Dehydrochlorination from cisor trans-1,2-Dichlorocyclododecane
94
Schematic Representation for the Possible Elimination
Pathways for Competitive Reaction of Two trans-1,2Dihalocycloalkanes with Complex Base
99
6.
CHAPTER I
INTRODUCTION
Elimination reactions are among the most widely studied reaction types in organic chemistry.
The chemical literature abounds
with reports of research dealing with the "elimination" of various
groups from substrates which yield new compounds. Most common
are those eliminations in which a proton and a leaving group are
removed from two neighboring carbon atoms, respectively.
This
1,2- or B-elimination is most often seen in alkene-forming eliminations.
However, alkynes, imines, and carbonyl compounds can also
be the products of 1,2-elimination reactions.
In this introductory
section, the fundamental mechanisms of alkene-forming eliminations
will first be surveyed.
Thereafter, mechanistic considerations
and the experimental techniques which are most commonly employed
in mechanistic elucidation of these reactions will be discussed.
Finally, the discussion will be focused upon the special area of
complex base-induced elimination reactions.
Mechanisms of Base-Promoted 1,2-Eliminations
Which Form Alkenes
Fundamental Mechanisms
In the course of an elimination reaction, the substrate molecule must undergo a series of bond breaking and bond forming steps.
Generally two bonds within the substrate molecule must be broken,
and at least one bond is formed as the substrate undergoes elimina-
tion to form the product. The timing of this bond rupture and
formation, together with other mechanistic considerations affords
a variety of mechanistic possibilities. These mechanistic possibilities include both concerted and stepwise processes, which can
vary in regard to the electronic distribution and atom geometries
in the transition state(s).
Three fundamental mechanisms, which
are located at the two extremes and in a central position along a
mechanistic spectrum have been proposed.
The actual mechanism
for a given elimination reaction can be thought of as being a
modification of one of these three general types.
The most common type of elimination is the base-induced loss
of HX (where X is a suitable leaving group) from adjacent carbon
atoms in an organic substrate. This reaction has been known for
12
2
many years ' and has been the basis of much study.
accepted mechanism
A presently
(Equation 1) accounts for the often observed
second-order kinetics (first order in base and first order in substrate) of many of these reactions by proposing that the removal
of the B-hydrogen by the base is synchronous with the loss of the
B
H
H
»
B
+ -C"
I
•C-
I
X
—C
I
I
C'
^ BH 4^C3ZC"+ X
(1)
leaving group X, Hanhart and Ingold
3
designated this mechanism E2,
signifying "elimination, bimolecular."
This mechanism stands central
in the mechanistic spectrum, since bond rupture and bond formation
are proposed to occur in concert. While the concerted nature of
bond breaking and forming is inherent in the E2 mechanism, the extent
to which the various bonds have been broken or formed may vary widely.
This variation will be discussed in more detail later in this introductory section.
In addition to the simultaneous loss of H and X in an elimination reaction, one can envision a process in which the leaving
group X has departed (i.e., C-X bond rupture is complete) prior
to loss of the proton.
Such a mechanism, the El, is illustrated in Equation 2,
,
H
^ 1 . 1 .
H:
-c—c- Z
I
^ -c
I
<
X
K
c
— >
H"^ + C ~ C _ - X
(2)
+
^-1
x'
This El (elin.ination, uniraolecular) mechanism was first proposed
to explain the overall first order (in substrate) kinetics observed
for certain eliminations from alkyl halides which occur in solution
4
in the absence of added base.
(Equation 2):
The mechanism involves two steps
a slow ionization of leaving group to form a cationic
species, followed by the fast loss of the B-proton to give the
olefin,
A third mechanistic possibility, which lies at the opposite
end of the mechanistic spectrum from the El type, is the ElcB
process (Equation 3),
"
2
+
-C
I
'
This mechanism involves the loss of the
^1
C- <
BH + -C
I
k
»
X
^-1
k
C-
> BH +^CIZ:C^ X (3)
proton to the base (C -H bond rupture) prior to the beginning of
C -X bond scission.
The ElcB mechanism (elimination, unimolecular,
conjugate base) cannot generally be kinetically distinguis'-^ed
from the E2 if the carbanion goes on to give the alkene product
much more rapidly than it reverts to starting material. If
k^>>k .[BH ], and the conditions required for a steady state approximation are met, the rate law for this mechanism becomes second-order
overall (first order in base and first order in substrate).
Such
a process is kinetically indistinguishable from that for an E2
reaction and the mechanism is termed ElcB irreversible. However,
if the return of the carbanion to starting material is much faster
than its collapse to give the product (k_^[BH ]>>k^), a rate law
is generated which is still first order in substrate and in base.
but has an inverse first order dependence on the conjugate acid
of the base.
A reaction with such a mechanism can be kinetically
distinguished from E2.
An ElcB mechanism of another type, which can also be kinetically
distinguished from the E2 has been proposed by Bordwell
Rappoport.
and
If the B-hydrogen of the substrate is very acidic
and the leaving group is poor, the substrate would then be expected
to be converted very rapidly to the carbanion which would only
slowly undergo loss of the leaving group to give the product.
In this case, a steady state approximation would be invalid (due
to the high concentration of the carbanion), and k^ would be rate
determining.
Under these circumstances, the rate law would be first
order in substrate, but zero order in the base, since further addition of base would not increase the concentration of carbanion.
Recently, Jencks et al,
has developed a concept of "enforced
concertedness," which he has applied to certain elim.ination reactions.
These workers
propose a merging of mechanism which is
induced by the instability of the proposed intermediate.
Thus a
change from an ElcB mechanism to an E2 mechanism might more appropriately be described as a transformation within a single mechanism
rather than a change between two coexiting mechanisms.
by Jencks,
As envisioned
the carbanion of the ElcB process becomes increasingly
unstable with substrate modification until its lifetim.e becomes
less than one vibrational period of the C-X bond.
Therefore, the
intermediate carbanion ceases to be an intermediate (in a potential
energy well along the reaction coordinate) and exists only as a
transition state.
Thus substrate modification which leads to in-
creasing instability of the carbanion, "forces" the loss of the
leaving group to be concerted with the loss of the proton.
This
concept raises the question of whether the discrete mechanistic
types previously described are individual mechanisms, or are actually portions of a mechanistic continuum.
The particular mechanism to be followed by a given elimination
reaction, is therefore determined by a wide variety of factors
which includes the base-solvent system and substrate structure.
In addition, there may be considerable mechanistic variation within
each of the three broad classes of elimination mechanism just
discussed.
In this treatment, it is impossible to describe all
aspects of these variations.
monograph on the subject.
2
The reader is referred to an excellent
However due to its pertinence, the
subject of mechanistic variation within the E2 mechanism will now
be addressed.
Variable E2 Transition State Theory
In the complex area of mechanistic elucidation of bimolecular
elimination, it became apparent early that a large number of elimination reactions appear to proceed by the same gross mechanism (E2).
However, orientation and reactivity differences among these reactions
suggest differences in transition state characters (and energy
differences between reactant and transition state) for the various
2
E2 reactions.
A comprehensive mechanistic theory, known as the
Variable E2 Transition State Theory, was the culmination of work
2 8 9
by several researchers, * * and was first comprehensively presented
in Bunnett's 1962 review.
In its original and most basic form,
the theory attributes the observed differences within the myriad
of E2 eliminations to changes in the relative extents of bond rupture of the carbon-hydrogen and carbon-leaving group bonds in the
transition state.
This "spectrum" of E2 transition states is illus-
trated in Figure 1.
B
B
B
I
I
I
I
I
H
H
I
•C:
H
I
I
I
I
C-
•cI
I
r
I
I
I
X
ElcB-like
1
Figure 1.
I
I
-Cr-rrr:CI
:
X
X
Central
El-like
2
3
Variable E2 Transition States
A continuum of E2 transition states can be pictured which range
from the ElcB-like variety j^, which has appreciable C-H bond rupture,
but very little C-X bond rupture, to the El-like type 2» in which
appreciable C-X bond scission has occurred, but relatively little
8
C-H bond rupture has taken place.
At the center of this continuum
lies the central E2 transition state 2^, which has syncronous C-H
and C-X bond rupture.
A further possible variation in transition state structure
must also be considered.
Although the degrees of rupture of the
C-H and C-X bonds may be well matched (central E2 transition state),
both bonds may be broken to a greater or lesser extent, which controls the degree of double bond formation.
Thus, central E2 transi-
tion states can have a high degree of double bond formation (productlike transition state), or very little double bond character (reactant-like transition state).
Variations of this type are best understood when seen in the
context of a More O'Ferrall diagram
(Figure 2).
This very popu-
lar 12 schematic representation of the potential energy surface
allows for all variations of E2 mechanisms (as well as the El and
ElcB mechanisms) to be represented.
While more detailed information on the use of these diagrams
in the study of elimination mechanisms is available in a recent
1o
review article,
a basic discussion of these plots follows:
Along the X and Y axes of the plot are represented the C-H and C-X
bond orders, respectively.
The Z axis (out of the plane of the
paper) represents the potential energy.
The reaction "pathway,"
in terms of C-X and C-H bond ruptures, can be plotted from reactants
(lower left-hand corner) to products (upper right-hand corner).
Thus, an El mechanism, which involves rupture of the C-X bond prior
I
B
I
t^
+ H-C—C+ + X
I
BH + C—C + X
I
/
/
El-like
/
Productlike
Central
/
/
/
u
p
u
Central
/
D.
3
/
U
/
X
I
/
h
B
Reactantlike
Central
I I
+ H-C—C-X
I I
Figure 2.
ElcB-like
/
C-H rupture
_ I
BH +
I
C—C-X
I
I
More O'Ferrall Potential Energy Surface for Elimination
Reactions
to rupture of the C-H bond would be represented by a pathway following the left-hand, then top borders of the diagram; while a syncronous E2 elimination would be represented by a diagonal pathway
directly from the lower left-hand comer to the upper right-hand
corner.
Placement of the transition state along a given reaction
pathway can give rise to representations of early (reactant-like)
transition states, or late (product-like) transition states.
Perturbations in transition state character influenced by
changes in substrate structure (a- or B-substituent effects, leaving
group effects, etc.) can be predicted by employing three rules in
conjunction with these plots:
12
(1) if species corresponding to a
10
corner along the reaction coordinate are stabilized, the transition
state is moved along the reaction coordinate away from the stabilized corner (Hammond effect); (2) if species corresponding to a
comer perpendicular to the reaction coordinate are stabilized,
the effect is to move the transition state toward the stabilized
corner; (3) if the stabilization is both along and perpendicular
to the reaction coordinate, the movement of the transition state
will be the vector resultant of the movements described in the
earlier rules.
Therefore, these plots can be employed in assessing the relative effects of variations in the reaction upon the reaction mechanism.
The power of these plots is their predictive nature.
The
predictions arising from the use of these plots can then be the
subject of experiment.
Probes of Mechanism and Transition State Structure
While predictions of transition state structure which conform
to the experimentally observed constraints are perhaps possible
in simple processes by use of the Hammond Postulate
13
or by apply-
14
ing such theoretical approaches as the Swain-Thorton Rules,
application of these principles to the complex bimolecular processes
at hand is not straight forward.
Therefore determination of the
reaction mechanism and transition state structure(s) must rely
heavily upon experimental techniques, a brief discussion of which
follows.
11
Variation in Structure of Elimination Substrate
Several techniques have been employed in the study of elimination reaction mechanisms which are based upon identifying changes
in reactivity as a function of structural modification.
One such
technique, which has wide applicability to a great many organic
reactions, is the linear free energy relationship which is known
as the Hammett equation
16
(Equation 4 ) .
log r^o
=
pa
(4)
Reactions of substrates which bear m- and £-substituted phenyl
groups can often by correlated with Equation 4, where k is the rate
(or equilibrium) constant for the reaction of the substrate that
contains a substituted phenyl group and k
is the rate (or equili-
brium) constant for the reaction of the corresponding substrate
with an unsubstituted phenyl group.
The constant p is characteris-
tic of a particular reaction and the reaction conditions.
Rho is
a measure of the sensitivity of the reaction to changes in electron
density at the reaction site.
The constant o is characteristic of
the particular substituent and its position on the phenyl group.
Sigma (o) values have been defined for a number of substituents.
2
Use of this technique is limited to those elimination substrates
which contain a phenyl group (usually attached to the 6-carbon).
Hammett o values have been tabulated for a large number of elimination reaction systems.
2
Introduction of substituent groups at the a- or B-carbons
of an elimination substrate has been utilized in mechanism elucida-
12
tion by several workers
W.
,B
H—C
I
^B
For example, the introduction of
,a
C—X
I
^a
an electron-withdrawing group at a B position (R. in 4) should
p
—
exert a stabilizing influence upon a developing negative charge
at Cg.
However, if the group is bulky, a steric effect might also
be envisioned (such as hindrance of approach of base).
Since the
source of such substituent effects often cannot be unambigiously
determined (being a mixture of steric, electronic, and possibly
other factors) mechanistic conclusions which are based upon these
substituent effects must be carefully weighed.
Careful attention
to experimental design can often enhance the utility of such data.
Bunnett et al.
*
have proposed an "element effect," which
is perhaps better described as the leaving group effect in elimina12
tion reactions. For example, it has been shown,
that a sequential
variation of leaving group identity (varying X in 4_) often leads to
large differences in reaction rates and product distribution (in
cases where two or more products are possible).
very useful in mechanistic elucidation.
Typically, the order of
leaving group reactivity is I>Br>Cl>>F for
halogenations.
Such data can be
base-promoted dehydro-
However, the magnitude of this effect and the
reactivity ordering are dependent upon the particular reaction
13
system.
This will become evident to the reader in the latter sec-
tions of this work.
Variations in Base and Solvent
Early in the study of elimination reactions, it was noted
that changes of base and/or solvent often had a pronounced effect
upon the reactions of a given substrate.
It has now been shown
that these effects arise from several sources.
Interpretation
of the results requires consideration of such factors as base
strength, base size, identity of the atom at the basic center,
2
and ion pairing or aggregation effects.
For example, simply
replacing an ion-paired base with a "free" base can induce large
variations in the orientation of eliminations from a common substrate.
20
Similarly dramatic rate and orientation effects have
been observed in many cases by a change in solvent for a given base,
such as t_-BuOK from DMSO to t^-BuOH.
21
Attempts to correlate rate data with base strength for a particular set of reactions was suggested more than 60 years ago
by Br^nsted.
22
Application of the Br«insted rate law (Equation 5)
to a general base catalysed reaction allows a proportionality constant e to be determined when k (reaction rate constant), K^ (ionization constant for the base, and G (a constant) are known.
However,
log k = B log K^ + log G
(5)
3 may be experimentally determined without the value of log G being
known.
Although B was formerly taken as a measure of the degree of
proton transfer to the base in the transition state, recent con-
14
siderations indicate that interpretation of these Br^nsted coefficients is more complex and that B may not be a reliable indicator
of transition state character.
Kinetic Isotope Effects
Kinetic isotope effects are reaction rate differences which
arise from the substitution of an atom in a substrate with a heavier
isotope of the same atom.
The theoretical basis of these effects
will not be described here. However, the reader is directed to
Saunders and Cockerill^s excellent discussion of these effects
2
as they relate to elimination reactions. The most common isotope
effects
which have been reported for elimination reactions are
deuterium isotope effects which arise from the replacement of
protium with deuterium in a substrate. Most commonly, primary
deuterium isotope effects (k^/k^ = 4-7) are encountered.
These
effects are often taken as indications of the extent of C-H bond
rupture in the transition state. The isotope effect varies in a
gaussian manner with the extent of proton transfer in the transition state. The maximum effect should be seen when a proton is
half transferred in the transition state. However, interpretation
of intermediate values for k-u/k-. is complicated by the gaussian
character of the effect.
For example, 25% and 75"! transfer of a
proton in the transition state would lead to similar values for
kp/k-.
A further complication is quantum mechanical "tunneling,"
which can lead to erroneous conclusions about transition state
character which are based solely upon deuterium isotope effects.
23
15
Recently, other kinetic isotope effects in elimination reactions
(notably
CI-
CI) have been investigated.
These investigations
have provided additional insight into the mechanisms of selected
elimination systems.
Stereochemistry of E2 Elimination Reactions
Introduction
Another important aspect to be considered in examining the
mechanistic aspects of elimination reactions is stereochemistry.
The spatial arrangement of the pertinent atoms in the transition
state has important consequences in terms of reaction rate and
product identity.
While a continuum of possibilities exist for
the location of the leaving group relative to the B-hydrogen in
the transition state, two extreme cases and two intermediate cases
have received special consideration (Figure 3 ) .
25
In the nomenclature of Klyne and Prelog,
the conformation
which is obtained by rotation about the C -C
'
bond to give a dihe-
u p
dral angle of 180° is termed anti-periplanar (5) ; while syn-periplanar (6) corresponds to a dihedral angle of 0° conformations
5 and 6 are often referred to as those for trans and cis elimination in the chemical literature.
However, the use of the c j ^ and
trans nomenclature in the context of mechanism is insufficient to
describe fully the stereochemical course of the reaction, and might
be more appropriately applied solely to the products of the reaction.
Two other conformational variations are also recognized.
16
H
Anti-periplanar
Syn-periplanar
6
X
Anti-clinal
Syn-clinal
7
Figure 3.
8
Newman Projections of Selected Elimination Stereochemistries
Anti-clinal (7)
and syn-clinal (8^) arrangements represent dihedral
angles of 120° and 60°, respectively.
The consequences of a particular transition state conformation
in a given reaction will become evident as the dichotomy of anti vs
syn elimination stereochemistries is examined.
Anti vs. Syn Elimination
The classic work of Cristol
26
with the benzene hexachloride
(1,2,3,4,5,6-hexachlorocyclohexane) isomers demonstrated the general
17
preference for anti elimination stereochemistry which has been
termed the Anti Rule.
In his study, Cristol
26
found that 9^ (which
has all the chlorine atoms trans to each other and is only capable
of syn elimination) reacted with base 7,000-24,000 times slower
H
CI
CI
H
CI
than did the other benzene hexachloride isomers (which had the
possibility of at least one anti elimination pathway).
The anti rule, while having great historical precedent, is
not without exceptions.
Certain bridged ring substrates were
shown to exhibit preferential syn elimination.
2
An example of
such a system which exhibits the typical conformational rigidity
that characterizes these substrates, is found in the eliminations
from the 9,10-ethanoanthracene derivatives jLO^ and U^.
The reaction
1^; X = CI, Y = H
11; X = H, Y = CI
18
of U^ with sodium hydroxide in 50% dioxane-ethanol at 110°C (syn
elimination) proceeds 7,8 times faster than does the analogous
reaction with 1^ (anti elimination).
27
Syn elimination stereochemistry is facilitated by certain
base-solvent combinations.
Generally, this effect has been attri-
buted to the degree of association of the base with its counter
12
ion.
28
Zavada, Svoboda, and Pankova,
in their detailed analysis
of t^-BuOK-induced elimination from 5-decyl tosylate, have demonstrated that the degree of base association influences the stereochemical course of the reaction (Table 1). When an effective K
com-
plexing agent (dicyclohexano-18-crown-6) was present for the reactions which were conducted in benzene or t^-BuOH, or the reaction
was run in a solvent that is more capable of efficient solvation
of the base counter ion (DMF), enhanced anti elimination was noted.
This result is consistent with the proposal that ion pairs (or
29
aggregates) of t-BuOK are the actual base species. Sicher
has
proposed a cyclic six-membered transition state 1^ which includes
electrostatic interactions between the base counter ion M and the
leaving group X to account for such favoring of syn elimination
/
_ C ^
C-
\
/
\
\
/
H
\
\
/
\
\
s
/
B-
— —
12
-M
/
/
X
i
19
TABLE 1
12
Effect of Solvent and Crown Ether on Syn and Anti Contributions
for _t-BuOK-Promoted Eliminations from 5-Decyl Tosylate
jL-BuOK
tl-'
n-Bu-CH
-n-Bu
>
cis and trans
%
conditions
n-BuCH=CH-n-Bu
%
%
%
anti—>
trans
syn—>
trans
anti—>
cis
syn—>
cis
33.6
12.4
50.4
3.6
C^H^'fxlE
6 6
63.9
4.1
29.2
2.8
_t-BuOH
24.8
4.2
68.2
2.8
^t-BuOH+CE^
67.1
4.7
26.7
1.5
DMF
73.2
2.8
22.6
1.4
^6"6
^CE = dicyclohexano-18-crown-6
20
relative to anti by associated bases. Examination of transition
state 2^2^ shows that the preference for syn elimination may be
explained on geometrical grounds. While the syn elimination provides for a cyclic transition state 1^, anti elimination cannot
involve such a cyclic transition state without inducing serious
strain in the transition state structure.
Orientation in E2 Elimination Reactions
In addition to the consequences of transition state structure
just discussed, the role of orientation in these eliminations must
also be addressed.
When elimination substrates are employed which
might give rise to two or more olefins, the question of orientation
arises.
For example, elimination from a 2-substituted
(Equation 6) can give rise to three products in theory.
CH.
CH^CHCH^CH.
>
CH^ CH
C=C
E
+
E
The three
H
;C=C
H
butane
+ CH2=CHCH2CH3
C6)
CH^
products illustrate the two types of orientation which are encountered in elimination reactions. When elimination products from a
common substrate differ as to the position of the double bond, the
21
products are said to have different positional orientation.
Thus,
cis- and trans-2-butene have the same positional orientation but
have a different positional orientation than does the 1-butene.
When the former pair are compared, the products are seen to differ
in the positions of the methyl groups on the double bond (cis vs.
trans).
When such orientation differences are addressed, these
differences are termed differences in geometric orientation.
When considering orientation differences in elimination products produced by a common mechanism from the same substrate, product proportion differences are attributed to differences in transsition state character for the various products.
Since all product
pathways diverge from a single substrate, transition state-reactant
energy differences must be due solely to differences in transition
state character for the various product pathways. Therefore orientation data can be significant in mechanism elucidation, ij_ a
common mechanism can be established for the competitive product
forming pathways.
Elimination to produce the less substituted alkene is termed
1 30
Hofmann orientation, ' while Saytzeff orientation is used to
describe the predominant formation of the more substituted olefin
(the thermodynamically more stable product).
31
Both positional
and geometrical orientation are influenced by the leaving group
identify, the base and solvent Identify, and the alkyl structure
of the substrate.
While a detailed discussion of the many factors
involved will not be undertaken in this section, the reader should
22
be cognizant of the role orientation considerations play in the
elucidation of elimination reaction mechanisms.
sions of these effects are available elsewhere.
Detailed discus2
Formulation of the Research Plan
Complex Base-Induced Elimination-Background
Caubere has popularized the use of sodium amide-containing
32 33
complex bases in organic synthesis. *
These bases, which are
composed of equimolar mixtures of sodium amide and ±n_ situ generated sodium alkoxide (or sodium enolate) in ethereal solvents,
such as tetrahydrofuran, have been shown to promote novel elimina32 33
tion reactions to form alkene, diene or aryne products. *
These highly aggregated sodium amide-containing complex bases
have been shown to efficiently promote syn eliminations from trans1.2-dihalocycloalkanes.
Caubere and Coudert
34
have reported that
the reaction of trans-1,2-dibromocyclohexane with NaNH2-NaO-t^-Bu
in THF at room temperature (Equation 7) gives 60% of 1-bromocyclohexene (syn elimination of HBr) and 36% of cyclohexene (debromination product).
However, when either the sodium amide or sodium
alkoxide base component was employed alone under the same reaction
conditions, 70-90% of the starting dibromide was recovered and only
34
traces of 1-bromocyclohexene or cyclohexene could be detected.
These results are startling when compared with those obtained for
similar eliminations employing more common alkoxide base-solvent
systems.^^
In these cases,"^^ synthetically useful quantities of
23
NaNH -NaO-_t-Bu
Br
(7)
H
THF, Room Temp.
H
Br
60%
1-halocycloalkene products are not produced.
36%
The 3-halocycloalkene
and 1,3-cycloalkadiene products predominate.
The remarkable ability of complex base to facilitate preferential syn elimination has been the subject of only limited mechanistic study.
A cyclic six membered transition state interaction 13
has been proposed
32 33 36
' *
to account for the observed results.
This representation is similar to Sicher's transition state ] ^
which has been proposed to explain the facility of syn eliminations
which are promoted by associated potassium alkoxide bases as was
discussed earlier.
In 13, where B is the base, M the base counter
13
24
ion, and X is the leaving group, an electrostatic interaction
between the leaving group (X) and the base counter ion (M) is
suggested to account for the observed favoring facilitation of
syn elimination.
Similar interactions of the base counter ion
and the leaving group are not possible in an anti elimination transition state due to geometrical considerations.
29
Importance of the alkoxide component identity in the complex
base upon the outcome of the reaction of trans-1,2-dibromocyclohexane has also been assessed.
37
Twenty-five different NaNH^-
NaOR combinations were utilized in reactions with the dibromo
substrate.
Results show that ramified alkyl groups (R of NaNH„-
NaOR) are important for producing the desired syn elimination.
38
Bartsch and Lee
investigated the possibility that the appar-
ent syn elimination was actually a base-catalyzed isomerization of
an initial anti elimination product (Equation 8).
Reaction of
Anti
' Hu
(8)
Br
Eliminatio
Isomerisation
H
H
Br
H
3-bromocyclohexene with complex base gave no detectable 1-bromocyclohexene.
This established that no isomerization was occurring
under the conditions of the complex base-promoted elimination reaction
25
39 40
in further work, Bartsch and Lee ' discovered a surprising
propensity for loss of the normally "poorer" leaving group in these
complex base promoted eliminations.
While an ordering of leaving
group reactivity of I>Br>Cl>>F is generally'''^*"''^ observed for
base-promoted dehydrohalogenations (consistent with Bunnett's
element effect for E2 eliminations
) , a reversal of this leaving
group ordering was observed in reactions of trans-1,2-dihalocycloalkanes which contained two different halogen atoms.
ment
Thus, treat-
39,40
'
of trans-l-chloro-2-fluorocyclohexane or trans-l-bromo-2-
fluorocyclohexane with NaNH2-NaO-_t-Bu in THF at room temperature
gave 85% of 1-chlorocyclohexene or 1-bromocyclohexene (-HF products) , respectively.
In neither case, was any 1-fluorocyclohexene
(-HC1 or -HBr product, respectively) detected.
Treatment of trans-
l-bromo-2-chlorocyclohexane with the same complex base, allowed
for a comparison of the relative propensities for dehydrochlorination and dehydrobromination.
Dehydrochlorination was found to
predominate over dehydrobromination with 54% of 1-bromocyclohexene
(-HC1) and 30% of 1-chlorocyclohexene (-HBr) being detected.
Lee and Bartsch further demonstrated that this preferential
loss of the normally poorer leaving group was confined to elimination reactions with syn stereochemistry.
Thus, reactions of 1-bro-
mo-l-chlorocyclohexane and cis-l-bromo-2-chlorocyclohexane with
NaNHp-NaO-_t-Bu in THF at room temperature gave 99% of 1-chlorocyclohexene.
26
Statement of Research Probl em
Although a few mechanistic aspects of complex base-promoted
elimination reactions have been investigated, the majority of the
factors which control these reactions remain to be determined.
Investigation of these factors is
definitely warranted due to
the unusual potential synthetic exploitation which these reactions
possess.
A program of research is envisioned which has as its initial
goal the identification of the effective base species for these
elimination reactions.
Variation of the oxyanionic component of
the complex base should have a pronounced effect upon the relative
rates of competitive dehydrohalogenation from a mixed halide substrate of the trans-1,2-dihalocyclohexane type, if the oxyanion
is indeed the effective base.
Since six-centered transition states of the type illustrated
in 13 have been proposed for complex base-induced elimination
reactions, a variation of ring size for the mixed trans-1,2-dihalocycloalkane substrate will be utilized to assess the effect of this
parameter upon the competitive dehydrohalogenation reaction modes.
Transition state structures for competitive dehydrochlorination
and dehydrobromination will be further characterized by the determination of leaving group and B-activating group effects.
An
analogous determination is envisioned for competitive dehydrofluorination vs. dehydrochlorination.
In order to ascertain the degree to which syn eliminations
are facilitated relative to corresponding anti elimination processes,
27
ratios of anti/syn rate constants will be determined for competitive reactions of a series of cis- and trans-1,2-dichlorocycloalkanes with complex base.
A search for possible steric interactions between the substrate
and the complex base is also proposed, as is the investigation of
the electronic requirements in the transition state at the a-carbon.
These experiments will provide mechanistic insight into this
unique type of elimination reaction.
Further mechanistic under-
standing is essential for full utilization of complex base-promoted
reactions as novel preparative reagents for the synthesis of hitherto
difficult-to-obtain elimination products.
CHAPTER II
EXPERIMENTAL SECTION
All compounds used in the preparation of substrates or authentic
samples of reaction products, or in the elimination reactions were
reagent grade unless otherwise specified.
All starting materials
in preparations of compounds and all reagents used in the elimination reactions (with the exception of some alcohols used in the
study of alkoxide variation, which came from various commercial
sources and were reagent grade) were obtained from Aldrich Chemical
Company, unless noted otherwise in the text of this chapter.
H NMR spectra were obtained using a Varian E14-360 or EM-360A
spectrometer.
IR spectra were obtained employing a Beckman Accu-
lab 8 spectrophotometer.
Elemental analyses were performed by
Galbraith Laboratories of Knoxville, Tennessee.
Three gas chromatographs were employed in the present research:
a Varian Aerograph Series 2400 flame ionization gas chromatograph
(isothermal column temperature capability), utilizing 1/8 inch
packed columns (Chromatograph A); an Antek Model 461 thermal conductivity gas chromatograph (isothermal column temperature) utilizing
1/4 inch packed columns (Chromatograph B); and a Varian Aerograph
Model 3700 capillary gas chromatograph with a FID detector and
temperature programming capability (Chromatograph C).
tographic columns were employed in the research:
Six chroma-
Column A - a
10 ft. X 1/8 inch column of 20% SE-30 on Chromosorb P, which was
utilized with Chromatograph A; Column B - a 5 ft. x 1/8 inch column
28
29
of 5% SE-30 on Chromosorb P, which was utilized with Chromatograph A;
Column C - a 20 ft. x 1/8 inch column of 15% Carbowax20M on Chromosorb P, which was utilized with Chromatograph A; Column D - a 10 ft.
X 1/4 inch column of 20% SE-30 on Chromosorb P, which was utilized
with Chromatograph B; Column E - a 0 . 2 0 m m x 2 5 m vitreous silica
capillary SE-30 column (WCOT) from SGE Corporation which was utilized
with Chromatograph C; and Column F - 20 ft. x 1/4 inch column of
15% Carbowax 20 M on Chromosorb P, which was utilized with Chromatograph B.
Detailed information on the gas chromatographic analyses
employed in this study is contained in a latter section of this chapter.
Preparation of Substrates
trans-1,2-Dibromocycloalkanes
trans-1,2-Dibromocyclobutane
The dibromide (0.34 g) was isolated by preparative GLPC (Column D
operated at 125°C) .^sa fortuitous side product (25%) of the reaction
of cyclobutene with N-bromoacetamide in 6 M aqueous HCl, which gave
trans-l-bromo-2-chlorocyclobutane as the major (75%) product.
Detailed information on the reaction to give the bromo chloride is
given vide infra.
analysis.
The dibromide gave a satisfactory elemental
Anal. Calcd for Q.^n^l2,ic^'. C, 22.45; H, 2.83.
Found: C,
22.55; H, 2.86.
trans-1,2-Dibromocyclopentane
40
The compound was available from the previous work by Lee.
30
Gas chromatographic analysis (Column A operated at 72°C) showed
the compound to be >98% pure.
trans-1,2-Dibromocvclnhfivanp
This dibromide had been prepared earlier by Lee,
and a sample
of the previously-prepared material was utilized after GLPC analysis
(Column A operated at 72°C) showed it to be >95% pure.
trans-1,2-Dibromocycloheptane
Cycloheptene (5.0 g) was treated with 8.0 g of bromine in
5.5 ml of carbon tetrachloride using the procedure reported for
the preparation of the analogous cyclohexyl analog.
'
Distilla-
tion of the crude material gave 10.3 g of the compound with bp 128130°/18 torr (Lit.
bp 137-138°/30 torr).
The homogeneity of the
product was demonstrated by GLPC (Column A operated at 100°C).
trans-1,2-Dibromocyclooctane
38
A sample prepared earlier by Lee
was employed.
A check of
purity by GLPC (Column A operated at 115°C) showed the material
to be >99% pure.
trans-1,2-Dichlorocycloalkanes
trans-1,2-Dichlorocyclopentane
A previously prepared
40
sample of the dichloride was employed.
Purity was ascertained by GLPC analysis (Column A operated at 72°C)
trans-1,2-Dichlorocyclohexane
40
Lee
prepared the dichloride previously.
A sample of this
previously prepared material was utilized after its purity was
31
demonstrated by GLPC analysis (Column A operated at
ll^'C),
trans-1,2-Dichlorocvcloheptane
Treatment of cycloheptene (5.0 g) with a slow stream of molecular chlorine in the dark, in analogy with a procedure reported
for the preparation of the cyclohexyl analog,
crude material.
gave 6 g of a
Careful distillation of this material gave 1.5 g
of the title compound (>99% pure by GLPC, Column A operated at
100°C), together with a 3.0 g fraction which was contaminated (20%)
with unidentified higher boiling compounds. Preparative GLPC of
the latter fraction (Column D operated at 200°C) yielded additional
pure dichloride.
The pure dichloride fraction boiled at 44-48°/
44
0.6 torr (Lit. bp 93-94°/ll-12 torr).
trans-1,2-Dichlorocyclooctane
A sample which had been prepared by Lee
38
was employed.
GLPC
analysis (Column A operated at 115°C) showed the compound to be
>99% pure.
trans-1,2-Dichlorocyclododecane
cis-Cyclododecene:
Treatment of a commercial sample (DuPont)
of 1,5,9-cyclododecatriene (95% cis, trans, trans; 5% isomers of
other stereochemistry) with 100% hydrazine hydrate, oxygen (from air),
and a catalytic amount of cupric acetate in 99% ethanol according
to the procedure of Nozaki and Noyori
tative yield of cis-cyclododecene.
gave an essentially quanti-
The material (bp 64-65°/0.6 torr,
Lit.^^ bp 132-134°/35 torr) was found to be >99% pure and free of
the trans isomer by capillary GLPC (Column E).
However, for a
32
parallel reaction (same scale) in which absolute ethanol was used
as the solvent and a very fast stream of air was employed as the
oxygen source (which resulted in a maximum reaction temperature
>50°C), significant contamination by the trans-cycloalkene was
evident.
The infrared spectrum of the product was consistent with
the spectrum previously recorded.
46
trans-1,2-Dichlorocyclododecane:
The dark reaction of cis-
cyclododecene (12,0 g) and molecular chlorine (slow stream) for
30 minutes during which the reaction temperature was not allowed
to exceed 40°C, followed by careful fractional distillation gave
the title dichloride.
The fraction boiling at 156-160°/1.5 torr
(3 g) was shown by capillary GLPC (Column E) to be >99% pure.
Another fraction (5.5 g) was shown by GLPC (same column and conditions) to be 92% pure.
The pot residue from the distillation
('V'lO g) was mainly composed of unidentified higher boiling compounds
(GLPC, same column and conditions).
The fraction of >99% purity
was submitted for elemental analysis. Anal. Calcd for ^]^2^22^'^2*
C, 60.76; H, 9.35.
Found:
C, 60.97; H, 9.37.
trans-l-Bromo-2-chlorocycloalkanes
trans-l-Bromo-2-chlorocyclobutane
Cyclobutene:
Cyclobutene was prepared in five steps from
cyclobutanecarboxylic acid (Ash Stevens, Inc.) by the method of
Weinstock, Lewis and Bordwell.
42
33
Cyclobutyl amine was prepared via a modified Curtis rearrangement from cyclobutanecarboxylic acid.
Thus, 28,4 g of the acid
was treated according to the reported procedure
47
with 50 ml of
H2S0^ and 20,15 g of sodium azide in 200 ml of chloroform for three
days at 40-50°C, followed by workup.
The resulting crude amine
('^'25 g as the syrupy amine hydrochloride) was employed directly
in the subsequent reaction.
Exhaustive methylation of the cyclobutyl amine was accomplished
first by refluxing 0.26 mole of the amine with 212 g of 88% formic
acid and 153 g of 35% formaldehyde solution overnight, as reported
48
previously.
48
Following the reported workup procedure
and distil-
lation, 10.6 g (bp 79-81°) of the N,N-dimethyl amine product was
obtained. Treatment of 10 g of this dimethyl cyclobutyl amine
49
with methyl iodide
(16.5 g) in 100 ml Et^O caused the immediate
precipitation of the quaternary ammonium salt which, ^^en filtered
and dried, was found to represent a quantitative yield based upon
the N,N-dimethyl amine starting material.
Replacement of hydroxide for iodide as the counter ion of the
quaternary amine salt was accomplished with Am.berlite IRA-400-OH
ion exchange resin according to a published procedure
analogy to a previous report.
42
and in
Thus, 24 g of the iodide (dissolved
in 100 ml H^O) was passed over 100 g of the exchange resin contained
in a 1 inch diameter X 3 ft. glass column,
Elution with water,
followed by evaporation yielded 17 g of the quaternary hydroxide.
34
Cyclobutene was prepared by the pyrolysis of the syrupy quaternary hydroxide.
Following the method of Roberts and Sauer,
the
syrupy quaternary amine hydroxide from the last step was added
dropwise to a flask held at 130-150°C, and under vacuum (50-70 torr,
aspirator).
The evolved gases were passed through 1 N HCl (aq) and
the cyclobutene was collected in a trap cooled by Dry Ice-acetone.
trans-l-Bromo-2-chlorocvclobutane:
Cyclobutene ("^3 g) which
had condensed in the Dry Ice-acetone trap was allowed to bubble
slowly through a mixture of 27.5 ml of 6 M HCl (aq.) and 7.6 g
N-bromoacetamide at -10°C by allowing the trap to warm slowly.
When the flow of cyclobutene ceased as the trap temperature reached
room temperature, dry nitrogen was swept through the trap and it
was heated to '^'50°C. The reaction mixture was worked up (ether
extraction, washing of the organic layer v;ith water, 10% aq. NaHCO,,,
10% aq, Na^CO-, and water) as specified for the preparation of
trans-l-Bromo-2-chlorocyclohexane
40
(vide infra).
Preparative GLPC
(Column D operated at 125°C) afforded 1.03 g of the pure trans-1bromo-2-chlorocyclobutane.
A small amount (0.34 g) of trans-1,2-
dibromocyclobutane was also collected as a side product. Anal. Calcd
for CH.BrCl:
4 o
C, 28.35; H, 3.57.
Found:
C, 28.54; H, 3.61.
trans-l-Bromo-2-chlorocyclopentane
A previously prepared
40
sample of this compound was available.
The purity was determined to be >98% by GLPC analysis (Column A
operated at 72°C).
35
trans-l-Bromo-2-chlorocyclohexane
The method of Lee was followed.
Simultaneously, cyclohexene
(32.8 g) was added dropwise and 55.2 g of N-bromoacetamide was added
in portions to 200 ml of 6 M HCl at -8°C.
Following the additions
(which took "^AO minutes, during which the temperature of the reaction mixture never exceeded -5°C) the mixture was allowed to stir
an additional 30 minutes.
After the stirring period was complete,
the organic layer was separated and the aqueous layer was extracted
twice with diethyl ether.
The combined organic fractions were
washed (water, 10% aq. NaHCO^), dried (CaCl2), and the ether was
evaporated under reduced pressure.
(Lit.
40
Distillation (bp 73-74°/4.5 torr
bp 48-49°/0.95 torr) of the residue gave 37.0 g of the title
compound, which was found to be >95% pure by GLPC (Column A operated
at 72°C).
trans-1-Bromo-2-chlorocycloheptane
Reaction of cycloheptene (5.0 g) with N-bromoacetamide and
6 M HCl under the identical reaction conditions and times described
above for the preparation of the cyclohexyl analog gave (following
distillation) 8.2 g of the title compound (>98% pure by GLPC,
Column A operated at 100°C).
18 torr.
The purest fraction boiled at 116-118°/
Anal. Calcd for C^H^2^^^1=
^' 39.74; H, 5.72.
Found C,
39.94; H, 5.69.
trans-l-Bromo-2-chlorocyclooctane
The title compound was available from a previous preparation.
A purity of ^99% was determined for this sample by GLPC (Column A
operated at 115°C).
38
36
trans-l-Chloro-2-fluorocycloalkanes
trans-l-Chloro-2-fluorocyrlnppnfanp
A sample of the chlorofluoride was available from previous
, 40
work.
A second preparation of the compound based upon the previ40
ously reported method,
(same scale and procedure used to prepare
the cyclohexyl analog, vide infra) proved to be troublesome, giving
an orange solid as the major product.
The desired compound which
was the minor product (25%) boiled at 90°C (Lit.^^ bp 62-63°/132
torr), and was shown to be >97% pure by GLPC (Column A operated at
72°C).
trans-l-Chloro-2-fluorocyclohexane
The method of Lee was followed.
40
Diethyl ether (50 ml) and
HF/pyridine (Aldrich) were mixed in a 500 ml polyethylene bottle
without a cap and cooled to 0°C.
N-Chlorosuccinimide (13.0 g)
was introduced with stirring, and then 8.0 g of cyclohexene was
added slowly while the temperature was held below 10°C.
Following
addition of all reaction components, the mixture was allowed to
warm to room temperature and stir for 30 minutes.
Then, the reac-
tion mixture was poured into 300 ml of ice-water.
The ether layer
was separated, washed (water, 10% of HCl), dried (CaCl2) and dis40
tilled to give 4.0 g of the product (bp 30-31°/3 torr. Lit.
bp
51-52°/l4 torr).
Purity was demonstrated to be >99% by GLPC (Col-
umn A operated at 72°C).
trans-l-Chloro-2-fluorocycloheptane
Treatment of cycloheptene (4.6 g) with
HF/pyridine and N-chloro-
succinimide in diethyl ether by the method described above for the
37
cyclohexyl analog gave 3.0 g of crude trans-l-chloro-2-fluorocycloheptane, which was contaminated with 15% of undetermined higher
boiling compounds.
Careful distillation gave 0.7 g of the material
(bp 82-83°/18 torr) which was shown (GLPC, Column A operated at
105°C) to be 95% pure. Anal. Calcd for C^H
Found:
ClF:
C, 55.81; H, 8.03.
C, 56.01; H, 8.26.
trans-l-Halo-2-methoxycycloalkanes
trans-l-Chloro-2-methoxycyclopentane
Cyclopentene (19.9 g), N-chlorosuccinimide (39.0 g) and dry
methanol (120 ml) were placed in a 250 ml round-bottomed flask
fitted with a reflux condenser to which a CaCl^ drying tube was
attached.
The reaction mixture was stirred magnetically at room
temperature for 3 days.
Following the reaction, the mixture was
poured into 400 ml of ice-water and extracted with Et20.
The ether
layer was washed successively with water, 10% aqueous HCl, and water
again.
The ethereal solution was dried over CaCl2 and distilled
to produce 10.0 g of the 98% pure (capillary GLPC, Column E) material
(bp 54-56°/10 torr), together with an additional 8.5 g of the title
compound which contained 7% of contaminants. Anal. Calcd for
C,H,,C10: C, 53.53; H, 8.24. Found:
6 11
trans-l-Bromo-2-methoxycyclohexane
C, 53.64; H, 8.34.
A sample of the title compound was available from previous work
by Lee.
This sample was employed in the present research after
analysis by capillary GLPC (Column E) showed the compound to be >99%
pure.
38
tran£-l-Chloro-2-methoxycyclohexane
Material prepared previously
38
was subjected to preparative
GLPC (Column D operated at 165°C) to remove contaminants. The
chromatographed material was shown to be >99% pure by capillary
GLPC (Column E).
trans-l-Fluoro-2-methoxycyclohexane
_trans-2-Fluorocyclohexanol:
was employed.
The method of Wittig and Mayer
Thus, reaction of cyclohexene oxide (28.0 g) and
potassium hydrogen fluoride (33.0 g) in diethylene glycol (55 g ) ,
followed by distillation (bp 80-85°/18 torr, Lit.^"*" bp 65-70°/14 torr)
gave 25 g of the product.
The material was shown to be >99% pure
by capillary GLPC (Column E).
trans-l-Fluoro-2-methoxvcvclohexane:
The methylation of trans-
2-fluorocyclohexanol proceeded according to a published report.52
Thus, 4.8 ml of Mel, 12.0 g of silver oxide, and 3.1 g of the
fluoro alcohol were stirred at room temperature in 30 ml of DMF for
24 hours. Distillation of the worked up material (bp 46°/12 torr,
Lit.
52
bp 41°/11 torr) gave trans-l-fluoro-2-methoxycyclohexane,
which was >99% pure (capillary GLPC, Column E).
tran3-l-Chloro-2-methoxycycloheptane
The method used to prepare trans-l-chloro-2-methoxycyclopentane
(vide supra) was followed exactly for the preparation of this compound,
with the exception that a smaller scale reaction was employed in the
present case, and the reaction was allowed to proceed four days.
Thus, cycloheptene (5.0 g), N-chlorosuccinimide (6.9 g) and 22 ml
39
of dry methanol were stirred at room temperature for 4 days.
Workup
(as reported above for the cyclopentyl analog) gave 4.5 g of the
crude product, which was ^^70% pure by GLPC analysis (Column E) .
A pure sample of the desired compound was isolated by preparative
GLPC (Column D operated at 200°C) and boiled at 99-101°/15 torr.
Anal. Calcd for CgH^^ClO: C, 59.07; H, 9.30.
Found: C, 59.33;
H, 9.27.
cis-1,2-Dichlorocycloalkanes
cis-1,2-Dichlorocyclopentane
The cis-dichloride was obtained from the corresponding epoxide
by reaction of 16.8 g of cyclopentene oxide and 78.7 g of triphenylphosphine in 100 ml of carbon tetrachloride, following the procedure
of Isaacs and Kirkpatrick.
53
Thus, the epoxide, triphenylphosphine,
and carbon tetrachloride were refluxed under nitrogen.
Periodically,
an aliquot of reaction mixture was removed, mixed with a small amount
of petroleum ether (30-60°), and examined for unconsumed epoxide
(GLPC, Column E ) . When no remaining starting material was observed
(2 hours), the mixture was allowed to cool, and was poured into
250-500 ml of 30-60° petroleum ether.
The supernant liquid was
decanted, the residual brown solid was ground (in portions) in a
mortar and pestle with some of the petroleum ether solution until
only light tan triphenylphosphine oxide crystals and the yellow
petroleum ether solution remained.
The solution was filtered to
remove the crystals, and the petroleum ether was evaporated under
40
reduced pressure to give the crude product. Distillation gave an
80% yield
of the desired compound, which was shown to be >98%
pure by GLPC (Column A operated at 72°C).
cis-1,2-Dichlorocyclohexane
A sample of this compound was available from previous work.
Purity was ascertained to be >99% by GLPC (Column A operated at 72°C).
cis-1,2-Dichlorocycloheptane
The title compound was prepared by the procedure
described
in detail for the cyclopentyl analog (vide supra) , with 0.2 mole
of cycloheptene being substituted for the cyclopentene.
was found to be complete after 3 days.
70°/l.l torr,
Reaction
The compound boiled at
was obtained in 80% yield, and was shown to be
99% pure by GLPC (Column A operated at 100°C).
cis-1,2-Dichlorocyclooctane
The cis-dichloride was prepared by the identical procedure
employed in the preparation of cis-1,2-dichlorocyclopentane (h scale),
with cyclooctene replacing cyclopentene.
after two days.
The reaction was stopped
Following a careful distillation to remove a trace
of the unconsumed epoxide, a 74% yield of the cis-dichloride was
56
obtained (bp 80-81°/0.8 torr. Lit.
bp 74°/l torr), which was shown
to be >95% pure by GLPC (Column A operated at 115°C).
cis-1,2-Dichlorocyclododecane
cis-Epoxycyclododecane:
The peracid epoxidation of cis-cyclo-
dodecene (see trans-1,2-dichlorocyclododecane for the synthetic
method) was accomplished using the method of Nozaki and Noyori.45
41
Thus, 9.0 g of the cis-alkene in 16 ml of methylene chloride was
added dropwise to 5.5 g of m-chloroperbenzoic acid in 66 ml of
methylene chloride at 25°C.
Following the addition, the reaction
was allowed to stir at room temperature overnight. The reaction
mixture was washed (10% Na2S02, 5% NaHCO^, dilute aq. NaCl, saturated
aq. NaCl) and dried (Na2S0^).
Distillation gave 5.5 g (bp 90-93°/
45
0.6 torr. Lit.
bp 88-90°/1.5 torr) of the desired product, which
was shown to be pure by capillary GLPC (Column E).
The IR spectrum
of the compound was identical to that previously reported.
cis-1,2-Dichlorocyclododecane:
from cis-epoxycyclododecane
The title compound was prepared
by the identical procedure employed
for the preparation of cis-1,2-dichlorocyclopentane (vide supra),
with the exception that a smaller scale was employed.
Thus, 5.5 g
of the epoxide, 11.9 g of triphenylphosphine, and 50 ml of carbon
tetrachloride were refluxed for 5 days, followed by the workup specified above for cis-1,2-dichlorocyclopentane.
A careful fractional
distillation of the 6.5 g of crude material gave a 70% yield of the
desired cis-dichloride [bp 145-147°/2.5 torr. Lit.
bp (mixture
with the trans isomer) 101°/1 torr].
11.12-Dichloro-9,10-dihydro-9,10ethanoanthracenes
trans-ll,12-Dichloro-9,10-dihydro9 ^10-ethanoanthracene
27 38
A sample of this compound, prepared previously by Lee, * was
available for utilization in the present research.
42
cis-11,12-Dichloro-9.10-dihydro9,10-ethanoanthracene
Treatment of anthracene with cis-1,2-dichloroethylene (Columbia
Organics) at 200°C for 24 hours in a sealed tube according to the
method of Cristol and Hause
27
gave the desired cycloaddition adduct.
Thus, 1.67 g of anthracene and 8.33 g of cis-1,2-dichloroethylene
were placed in each of three 26 mm X 200 mm thick-walled glass tubes,
which were sealed and heated for 24 hours at 200°C. Workup (according
to the published procedure
(10%) with anthracene.
27
) gave the desired compound, contaminated
Following repeated recrystallizations (CCl.)
a product was obtained (4.0 g) which was 95% pure by capillary GLPC
(Column E) and melted at 203° (Lit.^^ mp 203-204°C).
trans-2-Chipro-1-cyclohexyl Phenyl
Sulfide and Sulfone
trans-2-Chloro-1-cyclohexyl Phenyl
Sulfide
Treatment of cyclohexene (5.2 g) with a solution of phenylsulfenyl chloride (0.060 mole) in 60 ml of methylene chloride
according to the procedure (1/lOth scale) of Hopkins and Fuchs
afforded the title sulfide.
60
The crude product oil (14.1 g) , which
had been subjected to high vacuum to remove the residual solvent
gave a
H NMR spectrum which was identical to that published for
A 60
the compound.
trans-2-Chloro-l-cyclohexyl Phenyl Sulfone
Oxidation of the corresponding sulfide with m-chloroperbenzoic
60
acid according to the published procedure,
at six times the scale
43
of the published report, gave essentially a quantitative yield of
the crude sulfone, which was contaminated with 16% of 1-cyclohexen1-yl phenyl sulfone (capillary GLPC, Column E).
Careful recrystal-
lization of the crude product (hexane) gave a white solid with a H
NMR spectrum identical to the reported spectrum.
Miscellaneous Elimination Substrates
trans-l-Chloro-2-tosyloxycyclohexane
38
Lee
had previously prepared this sample. This material was
utilized following a check of the purity (97% by capillary GLPC,
Column E).
trans-[(2-Chlorocyclohexyl)oxy]trimethylsilane
trans-2-Chlorocyclohexanol:
The chlorohydrin was prepared in
82% yield by passing dry HCl into a solution of 50 g of cyclohexene
oxide in 50 ml of carbon tetrachloride until the solution was saturated, employing the procedure of Roberts and Hendrickson.
product chlorohydrin (bp 88-89°/10 torr. Lit.
The
bp 70-71°/7 torr)
was shown to be >99% pure by capillary gas chromatography (Column E).
trans-[(2-Chlorocyclohexyl)oxy]trimethylsilane:
Trimethyl-
silylation of the corresponding chlorohydrin with hexamethyldisilazane and a catalytic portion of concentrated sulfuric acid gave
the title compound in quantitative yield.
Thus, 5.0 g of the chloro-
hydrin, 3.6 g of hexamethyldisilazane, and 3 drops of concentrated
H SO
were stirred at room temperature for 1 hour, followed by
heating at 50°C for an additional hour.
After a 30 minute reflux
44
period, the reaction mixture was distilled under reduced pressure to
give a quantitative yield of the desired product with bp 105-106°/
8 torr.
Purity of the distilled product was determined to be >95%
by capillary gas chromatography (Column E).
The
H NMR spectrum
of the compound showed the following peaks:
6: 0.13 (s, 9H) ;
1.0-2.2 (n, 8H); 3.6 (n, 2H). Anal. Calcd for C H^^ClOSi: C,
52.27; H, 9.26.
Found:
C, 52.18; H, 9.28.
trans-2,3-Dichlorotetrahydropyran
The desired compound was prepared from 5-chloro-3,4-dihydro211-pyran (vide infra) by addition of anhydrous HCl to a benzene
solution of the starting material according to the procedure of
Stone and Daves.
Thus 1.2 g of the monochlorodihydropyran in
160 ml of dry benzene was treated with anhydrous HCl until the solution appeared to be saturated.
Following workup and evaporation
of the solvent, a quantitative yield of the desired material was
obtained.
The proton NMR spectrum of the product was in agreement
with that previously published.
62
The product was shown to be 99%
pure by capillary GLPC (Column E).
(E)-1,2-Dichloro-l-methylcyclohexane
The title compound was prepared by the chlorination of 1-methyl63
cyclohexene according to the procedure of Kharasch and Brown,
as previously employed by Hageman and Havinga.
64
Thus, to 8.0 g
of 1-methyl-l-cyclohexene, 8.0 g carbon tetrachloride, and 0.1 g
of azobisisobutyronitrile was added dropwise 10.8 g of sulfuryl
chloride in 8.0 g of carbon tetrachloride.
A one hour reflux period.
45
followed by distillation gave 16.0 g of the crude product. Preparative gas chromatography (Column D at 180°C)of the fraction boiling
at 41-44°/2.5 torr (Lit.^^ bp 66-67°/10 torr) gave pure (E)-l,2dichloro-1-methylcyclohexane.
Preparation of Authentic
Samples of Elimination Products
1-Bromocycloalkenes
1-Bromocyclobutene
trans-l-Bromo-2-chlorocyclobutane was treated with NaNH^NaO-t^-Bu
in THF at room temperature and worked up according to the standard
complex base reaction procedure (vide infra).
The resulting solution
was subjected to preparative gas chromatography (Column F operated
at 60°C) to give the desired 1-bromocyclobutene (as one of the
products), which was identified by comparison of GLPC retention
times with those reported previously.
The sample was shown to
be >99% pure by analytical GLPC (Coluirn C operated at 60°C) .
1-Bromocyclopentene
40
A sample, prepared previously by another worker, was employed
in the current research, following a purity determination (>99%)
by GLPC (Column A operated at 72°C).
1-Bromocyclohexene
40
The compound had been previously prepared by Lee.
,
A sample
from this previous synthesis was utilized after redistillation
(bp 44°/8 torr. Lit. ^ bp 63.l-63.4°/21 torr).
46
1-Bromocycloheptene
In analogy to the preparation of 1-bromocyclobutene, transl-bromo-2-chlorocycloheptane was treated with complex base (NaNH^NaO-t^-Bu) in THF at room temperature for 1 hr, followed by the standard
workup (vide infra).
Preparative gas chromatography (Column D operated
at 100°C) gave pure 1-bromocycloheptene.
determination
A micro boiling point
gave material with bp 185-186°/amb (Lit.^^ bp 66.5-
67.5°/13 torr).
1-Bromocyclooctene
A previously prepared
38
sample of the title compound was available.
This sample of 1-bromocyclooctene was utilized following a purity
determination (>99%) by GLPC (Column A operated at 115°C).
1-Chlorocycloalkenes
1-Chlorocyclobutene
The title 1-chloroalkene was collected from the preparative
gas chromatographic separation of the reaction mixture from which
1-broraocyclobutene was recovered (vide supra).
Thus, the complex
base reaction of trans-1-bromo-2-chlorocyclobutane gave 1-chlorocyclobutene
(>997)
and 1-bromocyclobutene , which was shown to be pure
by GLPC (Column C operated at 60°C) and identified by comparison
of GLPC retention times.
65
1-Chlorocyclopentene
40
A sample prepared by Lee
was employed in the present research
after GLPC analysis (Column A operated at 72°C) showed the compound
to be >99% pure.
47
1-Chlorocyclohexene
Treatment of cyclohexanone (100 g) with freshly sublimed phosphorus pentachloride (200 g ) , followed by addition of water according
to the procedure of Baude and Coles
*
gave a 50% yield of the
pure compound, bp 137°-139°/680 torr (Lit.
bp 141-143°/amb).
The
H NMR spectrum was identical to the published spectrum.
1-Chlorocycloheptene
In analogy to the preparation of 1-chlorocyclobutene from
trans-l-bromo-2-chlorocyclobutane, 1-chlorocycloheptene was isolated
by preparative gas chromatography (Column D operated at 100°C)
from the products of the reaction of trans-l-bromo-2-chlorocycloheptane with complex base.
Thus, treatment of the bromo chloride
with complex base (as is described in the section for the preparation
of 1-bromocycloheptene, vide supra) gave the desired compound.
The 1-chlorocycloheptene prepared by this method had a micro boiling
point^^ of 171-172°/amb (Lit.^° bp 75°/26 torr) and a 98% purity
as demonstrated by analytical GLPC (Column A operated at 100°C).
1-Chlorocyclooctene
A sample of 1-chlorocyclooctene, which had been prepared by
another worker,
38
was available for use in the present research.
GLPC analysis (Column A operated at 115°C) showed the compound to
be >99% pure.
(E)_l-Chlorocyclododecene
(E)-l-Chlorocyclododecene (0.5 g) was isolated by preparative
GLPC (Column D operated at 250°C) as the major product which resulted
48
from the reaction of cis-1.2-dichlorocyclododecane with complex base
(NaNH2-Na0-_t-Bu) in THF at room temperature for 30 minutes (standard
complex base elimination procedure, vide infra).
The product was
identified by the stereoselective dehalogenation of the vinyl chloride
to give cis-cyclododecene. which was then compared by capillary GLPC
(Column E) with an authentic sample of the cis-cyclododecene, employee
y-i
ing the method of Caubere et al.
and Nozaki et al.
Thus, into
a 10 ml round-bottomed flask (under argon) was placed 0.05 g of clean
lithium wire (washed with THF) and 3.1 ml of THF.
Then 0.21 ml of
dry _t-Bu0H was added, followed by the addition of 0.25 g of the vinyl
chloride in 1.0 ml of THF.
The reaction mixture was stirred for
one hour at room temperature, followed by a l4 hour reflux.
The
cooled reaction mixture was poured through a fluted filter, and the
recovered lithium metal was destroyed with 1-butanol.
Water (5 ml)
and hexane (5 ml) were added to the filtrate and the mixture was
shaken.
The resulting organic layer was analyzed by GLPC (Column E ) .
cis-Cyclododecene was the major product of the dehalogenation.
(Z)-l-Chlorocyclododecene
In analogy to the preparation of the E isomer, the title
compound (0.5 g) was isolated by preparative GLPC (Column D operated
at 250°C as the major product of the reaction of trans-1,2-dichlorocyclododecane with 0.5 M _t-BuOK-_t-BuOH at 50°C for 48 hours (standard
t-Bu0K-_t-Bu0H elimination procedure, vide infra) .
stereoselective dehalogenation procedure
Employing the same
58 71
'
described in the
sec tion on the preparation of the analogous E isomer (vide supra) ,
49
0.25 g of the material isolated by preparative GLPC was reduced to
trans-cyclododecene, thus identifying the substrate as the (Z)-lchlorocyclododecene.
1-Methoxycycloalkenes
1-Methoxycyclopentene
Treatment of 42.0 g of cyclopentanone with 53.0 g of trimethyl
orthofomate and 6 drops of concentrated H^SO, according to the
procedure of Hine and Arata
72
gave 17.0 g of the 95% pure material
(capillary GLPC, Column E) plus 9.0 g of 91% pure material, and
6.0 g of 85% pure material.
ketal was the contaminant.
95% pure
In each case, the corresponding dimethyl
The fraction determined by GLPC to be
boiled at 110-111°/amb (Lit,^^ bp 108-109/amb).
1-Methoxycyclohexene
Preparation of the title compound from cyclohexanone (52 ml)
and 54.7 ml of trimethyl orthoformate (with a catalytic amount of
p-toluenesulfonic acid) employing Lee's method
*
yielded 70 g
of a material which was contaminated with 33% of cyclohexanone
40
dimethyl ketal (as was the earlier reported preparation),
bp 137°/
amb (Lit.
bp 58°/28 torr).
Attempts to further purify the material
by preparative GLPC proved to be unsuccessful.
The
H NMR of the
product mixture identified the contaminant, and was in accord with
the previously
published spectrum.
40
1-Methoxycycloheptene
Treatment of 15.0 g of cycloheptanone with 14.2 g of trimethyl
orthoformate and 6 drops of concentrated H^SO, by the identical method
50
(appropriate scale) used in the preparation of 1-methoxycyclopentene
(vide supra), gave 15.0 g of 90% pure material, and 5.0 g of 75%
pure material (capillary GLPC, Column E).
The material which was
contaminated with 10% of the corresponding dimethyl ketal boiled
at 164°/amb (Lit.^^ bp 91-92°/87 to-r^.
3-Methoxycycloalkenes
3-Methoxycyclopentene
1,3-Cyclopentadiene
74
(30 ml, freshly distilled from the dimer)
in a 100 ml graduated cylinder was treated with anhydrous HCl until
the volume of the reaction mixture was 35 ml, in analogy to the
procedure of Alder and Flock.
The crude 3-chlorocyclopentene
(obtained as the residue from bubbling nitrogen through the reaction
mixture to remove the excess HCl) was used without further purification for the next step of the reaction.
method,
Employing the published
the crude chloroalkene (35 ml) was added dropwise to a
mixture of methanol (65.4 g) and sodium bicarbonate (57.1 g) at 0°C,
Following the addition, the reaction mixture was filtered.
The fil-
trate was diluted with water and extracted with diethyl ether.
Following a water wash and drying of the organic layer (CaCl2),
evaporation of the ether and distillation gave an 82% yield of the
desired compound.
The title compound, which was shown to be 98%
pure (capillary GLPC, Column E), boiled at 105°/amb (Lit.
108°/amb.
bp
51
3-Methoxycyclohexene
The sample prepared previously by Lee
was utilized.
Capillary
GLPC (Column E) showed the material to be uncontaminatedo
3-Methoxycycloheptene
Cycloheptene (5.0 g) and 2.3 g of N-bromoacetamide were refluxed
overnight in 15 ml of dry carbon tetrachloride.
Following filtra-
tion of the resulting succinimide and a careful fractional distillation, 1,0 g of crude 3-bromocycloheptene (bp 75°/45 torr) was obtained.
The crude 3-bromocycloheptene (1.0 g), 10.5 g of sodium bicarbonate,
and 12 ml of methanol were stirred overnight. Following the reaction,
the reaction mixture was poured into 50 ml water and extracted twice
with 20 ml portions of diethyl ethero
The organic layer was washed
(saturated aq. NaCl), dried (CaCl^), and subjected to rotary evaporation to give 1 g of the crude product which was contaminated with
cycloheptene.
Preparative GLPC (Column D operated at 150°C) gave
the pure compound (bp 160°/amb by micro boiling point determination,
Lit.^^ bp 56°/18 torr.
Cyclohexen-1-yl Phenyl Sulfides and Sulfone
1-Cyclohexen-l-yl Phenyl Sulfide
The title sulfide was prepared by the base-catalyzed isomerization of 2-cyclohexen-l-yl phenyl sulfide (vide infra) according to
the procedure of Hopkins and Fuchs.
Thus, 0,25 g of 2-cyclohexen-
l-yl phenyl sulfide, 0.03 g of _t-BuOK and 1.3 ml of DMSO v/ere placed
in a 2.0 ml volumetric flask.
After shaking, the flask was allowed
52
to stand overnight.
After reaction, the contents of the flask were
poured into 13 ml of 2% aqueous HCl and extracted with diethyl ether.
The ether layer was washed (water, saturated aq. NaCl) and dried
(CaCl2).
The
Evaporation of the solvent gave 0.25 g of a yellow oil.
H NMR spectrum of the resulting oil was identical with the
published spectrum for this compound.
A GLPC analysis of the
oil (Column C operated at 140°C) showed it to be 97% pure.
2-Cyclohexen-l-yl Phenyl Sulfide
Treatment of 1.13 g of trans-2-chloro-l-cyclohexyl phenyl
sulfide with 1.52 g of DBU at 120°C for 9 hours, according to a
published procedure,
gave 0.97 g of 2-cyclohexen-l-yl phenyl sul-
fide, which was contaminated with 5% of the 1-cyclohexen-l-yl isomer
(GLPC, Column C operated at 140°C).
The
H NMJl of the product
sulfide was in agreement with the published spectrum.
60
1-Cyclohexen-l-yl Phenyl Sulfone
The slow addition of 2.4 g of DBU to trans-2-chloro-l-cyclohexyl phenyl sulfone (4.0 g) in 20 ml of methylene chloride at 0°C
followed by 30 minutes of stirring at room temperature and workup
according to the procedure of Hopkins and Fuchs
title compound.
be 97''< pure.
gave 2.7 g of the
Capillary GLPC (Column E) showed the compound to
The ^H NMR spectrum of the product sulfone is in agree-
ment with the published spectrum.
60
53
Miscellaneous Elimination Products
ll-Chloro-9,lO-dihydro-9,10ethenoanthracene
A sample of the title compound was available from previous work
38
by Lee
and was utilized in the present research after it was
demonstrated to be free of Impurities by GLPC analysis (Column E) .
(1-Cyclohexen-l-yloxy)trimethylsilane
The procedure of House et al.
was employed.
Cyclohexanone
(24.5 g) was refluxed for 4 hours with 32.6 g of trimethylsilane
and 60.6 g of triethylamine in 100 ml of DMF. Workup and distillation gave a 97% yield of the desired trimethylsilyl enol ether
(bp 176°/amb, Lit.
bp 74-75°/20 torr).
A purity of 96% was
demonstrated by capillary GLPC (Column E).
5-Chloro-3,4-dihydro-2H-pyran
The modified procedure of Riobd
was employed.
Dihydropyran
(50 g) in 100 ml of carbon tetrachloride at -5°C was treated with
molecular chlorine in the dark until the solution appeared to be
saturated.
The reaction mixture was then distilled, with solvent
being collected first, followed by the material which boiled from
100-150**C. Pyrolysis of the latter fraction according to the standard
procedure,
followed by distillation gave the desired product in
crude form, together with an unidentified contaminant. Treatment
of this crude reaction mixture with a two-fold excess of aqueous
silver nitrate, followed by filtration, extraction with methylene
chloride, drying (CaCl2), and distillation (bp 137°/amb, Lit.^^
bp 139-140°/amb) gave a 47% yield of the >99% pure product (capillary
GLPC, Column E).
54
Procedures for Elimination Reactions
Complex Base-Induced Eliminations
Preparation of Complex Base
'^^
Under nitrogen in a glove bag, 0.38 g (9.80 mmol) of NaNH2
(Fisher, powder) was weighed into a 25 ml one-necked (standard
elimination procedure) or three-necked (competitive elimination
procedure, sidearms of flask were fitted with rubber septa) roundbottomed flask fitted with a reflux condenser.
To the top of the
reflux condenser was attached a T-tube through which a slow flow
(5 ml/min) of nitrogen was passed during the reaction.
The activat-
ing compound [4.90 mmol; t_-Bu0H (Fisher) unless specified differently]
and 8.0 ml of dry tetrahydrofuran (MCB, distilled from LiAlH.)
were added to the flask, and the mixture was stirred magetically
for 1 h at room temperature (or at the temperature of the subsequent
elimination reaction, if different).
Standard Complex Base Elimination
Procedure^^'^^
To the prepared complex base mixture was added 3.26 mmol of
the elimination substrate (and other compounds, if specified). After
addition of the substrate to the stirred heterogeneous reaction
medium at room temperature (or at a higher temperature, or while
the flask was partially immersed in water in a Bransonic 220 ultrasonic cleaning bath, if specified), the reaction was monitored by
periodic removal of 2 ml aliquots that were analyzed directly for
unreacted substrate by GLPC.
When the elimination substrate had
been consumed, the reaction mixture was poured into 70 ml of ice-
55
water in a 100 ml volumetric flask.
The reaction flask was rinsed
with a small amount of diethyl ether. The rinsings and additional
diethyl ether (total of 30 ml) were added to the ice-water mixture.
An appropriate internal standard was added, and after being shaken,
the flask was allowed to stand overnight in a refrigerator. The
organic layer was then analyzed by GLPC for elimination products.
Competitive Complex Base Elimination Procedure
To the prepared complex base was added 1.63 mmol each of two
elimination substrates.
The heterogeneous reaction medium was stirred
magnetically at 20.0°C (or at a higher temperature, if specified).
At timed intervals a 1.0 ml sample of the reaction mixture was
removed from the reaction vessel via the rubber septum with a
1.0 ml tuberculin syringe with large bore needle and was added to
4.0 ml of THF which contained a known amount of internal standard
in a 5 ml volumetric flask that was suspended in a Dry Ice-acetone
bath.
After four such aliquots were removed (within 10-30 minutes) ,
the remainder of the reaction mixture was discarded.
After being
shaken, the diluted samples of reaction mixture were held at -78°
until GLPC analysis which involved direct injection of the sample
at Dry Ice-acetone temperature into the gas chromatograph.
Control Experiments
To the prepared complex base was added an authentic sample
of the elimination product(s) and, in some cases, added inorganic
compounds.
The heterogeneous reaction mixture was stirred at
room temperature (or a different temperature, if specified) for a
given time interval. Then, the reaction mixture was quenched with
56
water as specified in the Standard Elimination Procedure; or aliquots
were removed and quenched at low temperature as specified in the
Competitive Elimination Procedure (vide supra).
Following quenching
of the reaction mixture, GLPC analysis of the samples revealed
whether decomposition and/or isomerization of the elimination products (s) had taken place.
Eliminations Induced by Potassium
t-Butoxide in t-Butanol
Preparation of _t-Bu0K-^-Bu0H
tert-Butyl alcohol (Fisher) was distilled three times from
potassium metal (Fisher)o
Into a round bottom flask which was
fitted with a reflux condenser and a magnetic stirrer and kept
under a slow stream of nitrogen
was placed 25o5 ml of dry t-BuOH.
Potassium metal (1.0 g) was weighed and cut into 4-6 smaller pieces
under xylene.
Over a period of 10-30 min pieces of the metal were
removed from the xylene, swirled in a small beaker filled with dry
^-BuOH until they were shiny, and added to the reaction vessel.
After all of the metal was added, the reaction mixture was stirred
until no more potassium metal could be seen.
It was often necessary
to warm the reaction vessel near the end of the reaction, to facilitate complete dissolution of the metal. A sample of the prepared
base-solvent was removed, standardized against 0.1000 N HCl with
phenolphthalein indicator, and adjusted by dilution with dry ^-BuOH
until the base-solvent solution was 1.00 M.
Solutions of lesser
concentrations were prepared by further dilution.
If the base-solvent
57
solution became yellow, the solution was discarded.
Fresh base-
solvent solution was prepared just prior to each use, and any unused
portion discarded.
Elimination Procedure for _t-BuOK-t-BuOH
An elimination substrate (1,63 mmol) was weighed into a 5 ml
volumetric flask.
Freshly prepared _t-BuOK-_t-BuOH (0,50 M unless
otherwise specified) was added to the mark and the flask shaken.
The flask was suspended in a constant temperature bath (50,0°C
unless specified differently).
Periodic removal of 2 yl samples
and GLPC analysis were used to measure consumption of the elimination substrate.
Following the reaction period, the mixture was
poured into ice water, worked up and analyzed by GLPC by the same
procedure which was given under the Standard Complex Base Elimination Procedure (vide supra).
Control Experiments
The elimination reaction procedure just outlined was followed,
with the exception that an authentic sample of the elimination product (s) was substituted for the elimination substrate. Analysis
by GLPC was undertaken to detect decomposition and/or isomerization
of the elimination product(s).
Gas Chromatographic Analysis
The gas chromatographs and columns employed in this work have
been described in detail in the introductory paragraphs of this
chapter.
Chromatograph B was employed in preparative gas chroma-
tographic applications, while analytical GLPC was accomplished
58
with Chromatographs A and C,
Compound Purity Determinations
GLPC was routinely employed in the determination of elimination
substrate and authentic elimination product sample purity.
In the
sections of this chapter which deal with the preparation of these
compounds, column specifications (and the column operating temperature if Chromatographs A and B were utilized) are given.
In the
case of those compounds analyzed by Chromatograph C (capillary
chromatograph)no column operating temperature is given, since temperature programming was utilized (generally with an initial temperature
of 50°C, a final temperature of 250°, and a program rate of 4°/minute).
Purity values were based upon relative peak areas and were not corrected for molar response differences.
In many cases an SE-30 column of moderate length (which was
very efficient in the resolution of halogenated hydrocarbons) was
employed with Chromatograph A for assessing the purity.
In the
latter stages of this research, Chromatograph C (employing a column
with a similar methyl silicone gum rubber packing material) was
routinely employed.
In those cases in which unsatisfactory resolu-
tion was encountered utilizing either of the previously mentioned
modes of GLPC determination, a long carbowax 20 M column (Column C)
was used in conjunction with Chromatograph A.
Analysis of Elimination Reaction
Mixtures
Analysis of aliquots of the reaction mixture from an elimination
reaction
or of ether extracts from the reaction mixture after work up
59
was accomplished by gas chromatography.
Analysis of the reaction
mixtures for the trans-dihalocyclobutyl and trans-2-chlorocyclohexyl
phenyl sulfide systems utilized Column C operated at 50-100° on
Chromatograph A.
Chromatograph A and either Column B (analysis of
aliquots of reaction mixture) or Column A (analysis of ether extracts
of worked-up reaction mixtures) operated at 30-150°C were utilized
in the analysis of the cis and trans-dihalocyclopentyl (most),
-hexyl, -heptyl, and -octyl systems. All other analyses utilized
Chromatograph C operated at 50-250° (generally employing a temperature
program as follows:
initial temperature 50°, final temperature 250°,
program rate 4°/min).
Detailed information on which chromatograph
was utilized in the analysis of a specific compound is readily
available by consulting the molar response table provided below.
Molar Response Studies
In order to correct for differences in detector response, molar
response corrections have been applied to calculations of product
yields and product ratios reported in this work.
correction factor has been defined
40
The molar response
in Equation 9 for a particular
moles of internal standard
peak area of compound
Molar Response =
— —
~ X
(9)
moles of compound
peak area of internal
standard
compound relative to given internal standard compound and gas chromatograph.
Table 2 lists (in alphabetical order) the internal standard, gas
chromatograph, and value of the molar response for each of the compounds in this study for which data has been used in calculations
60
TABLE 2
Molar Response Values
Compound
Internal
Standard
Gas
Chromatograph
Molar
Response
trans-l-bromo-2-chlorocyclobutane
toluene
A
0.575
trans-l-bromo-2-chlorocycloheptane
a-xylene
A
0.680
trans-l-bromo-2-chlorocyclohexane
toluene
A
0.657
trans-l-bromo-2-chlorocyclooctane
£-xylene
A
0.690
trans-l-bromo-2-chlorocyclopentane
£-xylene
A
0.795
1-bromocyclobutene
toluene
A
0.641
1-bromocycloheptene
o-xylene
A
0.824
1-bromocyclohexene
toluene
A
0.720
1-bromocyclooctene
£-xylene
A
0.862
1-bromocyclopentene
£-xylene
A
0.680
trans-l-bromo-2-methoxycyclohexane
toluene
C
0.850
1-chlorocyclobutene
toluene
A
0.620
(E)-l-chlorocyclododecene
£-xylene
C
1.09
(Z)-l-chlorocyclododecene
£-xylene
C
1.09
1-chlorocycloheptene
o-xylene
A
0.806
1-chlorocyclohexene
toluene
A
0.699
1-chlorocyclooctene
o-xylene
A
0.849
1-chlorocyclopentene
£-xylene
A
0.661
1-chlorocyclopentene
£-xylene
C
0.647
ll-chloro-9,10-dihydro-9,10ethenoanthracene
triphenylmethane
C
0.867
5-chloro-3,4-dihydro-2H-pyran
toluene
C
0.508
61
TABLE 2 (Continued)
Compound
Internal
Standard
Gas
Chromatograph
Molar
Response
trans-l-chloro-2-fluorocvcloheptane £-xylene
A
0.701
trans-l-chloro-2-fluorocyclohexane
A
0.851
trans-l-chloro-2-fluorocyclopentane £-xylene
A
0.546
trans-l-chloro-2-fluorocyclopentane £-xylene
C
0.556
tran9-l-chloro-2-methoxycyclohexane toluene
c
0.870
(1-cyclohexen-l-yloxy)trimethylsilane
toluene
c
0.792
1-cyclohexen-l-yl phenyl sulfide
toluene
A
1.20
2-cyclohexen-l-yl phenyl sulfide
toluene
A
1.00
1-cyclohexen-l-yl phenyl sulfone
toluene
C
1.30
trans-1,2-dibromocycloheptane
£-xylene
A
0.774
trans-1,2-dibromocyclohexane
toluene
A
0.740
trans-1,2-dibromocyclooctane
£-xylene
A
0.729
trans-1,2-dibromocyclopentane
£-xylene
A
0.845
trans-1,2-dichlorocyclododecane
£-xylene
C
1.00
cis-1,2-dichlorocycloheptane
£-xylene
A
0.952
trans-1,2-dichlorocycloheptane
£-xylene
A
0.857
cis-1,2-dichlorocyclohexane
toluene
A
0.893
trans-1,2-dichlorocyclohexane
toluene
A
0.826
cis-1,2-dichlorocyclooctane
£-xylene
A
0.697
trans-1,2-dichlorocyclooctane
£-xylene
A
0.791
cis-1,2-dichlorocyclopentane
£-xylene
A
0.730
trans-1,2-dichlorocyclopentane
£-xylene
A
0.700
tolune
62
TABLE 2 CContinued)
Compound
Internal
Standard
Gas
Chromatograph
Molar
Response
trans-1,2-dichlorocyclopentane
o-xylene
C
0.619
cis-11,12-dichloro-9,10-dihydro9,10-ethanoanthracene
triphenylme thane
C
0.850
trans-11,12-dichloro-9,10-dihydro9,10-ethanoanthracene
triphenylme thane
C
0.843
(E) -1,2-dichloro-l-methylcyclohexane
toluene
trans-1-fluoro-2-methoxycyclohexane
toluene
C
0.907
1-methoxycycloheptene
toluene
C
0.913
3-methoxycycloheptene
toluene
C
0.926
1-methoxycyclohexene
toluene
C
0.792
3-methoxycyclohexene
toluene
C
0.800
1-methoxycyclopentene
o-xylene
C
0.580
3-methoxycyclopentene
o-xylene
C
0.607
1.37
63
that require a molar response correction.
Elimination reaction
product, substrate, and internal standard peak areas were measured
by electronic integration.
CHAPTER III
RESULTS AND DISCUSSION
Synthesis of Elimination Substrates
The substrates utilized in the elimination reactions of interest
in this study were generally known compounds, which were prepared
by literature methods, or by extensions of well-known reactions.
Particular compounds were characterized by comparison of their
physical properties with the values reported in the literature.
In cases where a new compound was prepared, elemental analyses
for carbon and hydrogen were conducted.
Carbon-hydrogen elemental
analyses were also obtained in some cases where a known compound
was prepared by a new synthetic method, or in cases where insufficient
physical and spectral data were available in the literature for
comparison with the data obtained for the experimentally prepared
material. Substrate purity, in all cases, was determined by gas
chromatographic analysis.
The trans-1,2-dihalocycloalkanes were prepared by the ionic
anti addition of halogen (or Jri^ situ-generated
to the corresponding alkenes.
mixed halogens)
trans-1,2-Dibromo- and trans-1,2-
dichlorocycloalkanes were prepared by the direct addition of molecular
bromine or chlorine, respectively, to the cycloalkenes.
Treatment
of the cycloalkenes with N-bromoacetamide and hydrochloric acid
(to give in situ bromine chloride
2-chlorocycloalkanes.
81 8'^
' )
produced the trans-1-bromo-
Preparation of the trans-l-chloro-2-fluoro64
65
cycloalkanes was accomplished by treatment of the cycloalkenes with
OO
N-chlorosuccinimide and Olah's
reagent.
QA
*
hydrogen fluoride-pyridine
However, repeated attempts to prepare the cyclooctyl
analog by this method proved futile.
The necessary cis-1,2-dichlorocvcloalkanes were generally prepared from the corresponding cycloalkene oxides by treatment with
triphenylphosphine and carbon tetrachloride according to an exten54
53
sion
of a published procedure.
The precursor epoxides were
either commercially available, or were prepared from the cycloalkenes
by reaction with m-chloroperbenzoic acid.
Treatment of anthracene with cis- or trans-1,2-dichloroethene
under sealed tube conditions gave the cycloaddition adducts, cisand trans-11,12-dichloro-9.10-dihydro-9,10-ethanoanthracene. These
27
Diels-Alder type reactions were reported previously.
Attempts
to prepare the trans-dihalo derivatives using the methodology employed
in the cycloalkyl systems (i.e. ionic addition of halogen or mixed
halogen to 9,lO-dihydro-9,10-ethenoanthracene) met with failure.
This result is consistent with reports by others of Wagner-Meerwein
rearrangements which take place in this dibenzobicyclo[2.2.2]octadiene
85 86
system in the presence of oxidizing agents or radical sources. '
trans-2-Chloro-l-cyclohexyl phenyl sulfide and the corresponding
sulfone were obtained by treatment of cyclohexene with phenylsulfenyl
chloride (generated ^H situ from thiophenol and N-chlorosuccinimide)
to give the sulfide, followed by peracid oxidation to provide the
sulfone.
60
66
:CH.)
2 n
Substrates of the type shown above (where X = halogen) were
either prepared by direct addition to the corresponding alkene, or
by the replacement of the hydroxyl hydrogen of the corresponding
halohydrin (R = H) with some group (R = Me, Ts, TMS). Detailed
information on the specific methods employed in the preparation
of these compounds is available in the Experimental Section.
trans-2,3-Dichlorotetrahydropyran was prepared from 5-chloro3,4-dihydro-2E-pyran, which had been originally obtained from the
corresponding dihydropyran.
(E)-1,2-Dichloro-l-methylcyclohexane
was prepared by the radical addition of chlorine to 1-methylcyclohexene.
Mechanistic Features of Complex
Base-Induced Elimination
Relative to more commonly encountered alkene-forming elimination
systems, comparatively little is known about the mechanistic features
of complex base-promoted elimination reactions. The synthetic utility
of the stereospecific and facile syn elimination commonly seen with
67
complex base has been noted.
*
However, many of the mechanistic
factors of these reactions remained unexplored as the present work
was undertaken.
40
Previous work by Lee
has established that syn 1,2-elimination
is the reaction mode in the reaction of complex base with several
trans-1,2-dihalocyclohexanes. rather than a base-catalyzed isomerization of the product(s) of anti elimination to give apparent syn
elimination products.
In addition, a mechanistic possibility which
has for its key reactive intermediate a carbene has been ruled out
40
by Lee on the basis of experiment.
Determination of the primary
deuterium isotope effect by internal competition for elimination
by complex base (NaNH.-NaO-t^-Bu) in THF at room temperature from
14 and L5^ gave (after applying small corrections for product decompo-
Br
H >
D
Br
1^
( CI H
i^
sition) k„/k^ values of 6 and 4 for eliminations from 1^ and 15,
respectively.
Thus, the evidence obtained by Lee appears to
support an E2 mechanism which demonstrates highly specific syn
stereochemistry.
Additional work by Lee and Bartsch
39 40
* demonstrated a further
surprising mechanistic feature of complex base-induced elimination.
While an ordering of I>Br>Cl>>F has been often observed
*
for
leaving group reactivity in base-promoted dehydrohalogenations
68
(
41
(.operation of Bunnett's
leaving group "element effect"), a reversal
of this leaving group ordering was reported
*
for complex base-
promoted syn eliminations from certain trans-1,2-dihalocyclohexanes.
Thus, treatment of trans-l-bromo-2-chlorocyclohexane with NaNH2Na0-_t-Bu in THF at room temperature for 24 hours gave 52-55% of
1-bromocyclohexene (-HC1 product) and 30-31% of 1-chlorocyclohexene
(-HBr product).
The comparison of the effect of leaving group
identity becomes more striking when either trans-l-chloro-2-fluorocyclohexane or trans-l-bromo-2-fluorocyclohexane was treated with
complex base under the conditions just described.
Elimination from
either substrate gave 85% of the product of dehydrofluorination
(1-chlorocyclohexene or 1-bromocyclohexene, respectively) and no
1-fluorocyclohexene.
Thus, dehydrofluorination predominates in these
reactions, and overall a reversal of the "normal" leaving group
ordering was seen. A six-centered transtion state of type Y^ has
39 40
been postulated to explain this effect. '
The present work reports research undertaken to more fully
probe the character of these reactions.
Specifically, several areas
of study were identified at the beginning of the present work, and
are discussed below.
Preliminary work by Caubere and others
37
had shown that variation
of R in the complex base NaNH2-NaOR produced an effect upon the
relative proportions of debromination and dehydrobromination obtained
from the reaction of trans-1,2-dibromocyclohexane.
These authors
found 37 that more ramified R groups enhanced the proportion of dehydrobromination.
In light of the discovery by Lee and Bartsch
39 40
' of
69
the reversal of the normal leaving group ordering, a study of the
effect upon the relative propensity for dehydrobromination and
dehydrochlorination from trans-l-bromo-2-chlorocyclohexane due
to alkoxide component substitution in the complex base (with various
sodium alkoxides, enolates, and related compounds) was undertaken.
The results of this study, which provides definitive information
on the identity of the active base in the complex base, are given
in detail in a later subsection of this chapter.
Both the unique syn elimination stereochemistry and the surprising
loss of the normally poorer leaving group have been attributed to a
transition state (like 13) which entails a six-centered atom set having an important interaction between leaving group and the
counterion (Na ) of the base, in addition to the interaction of base
and proton.
Since the ability of an elimination substrate to conform
itself to the requirements of such a transition state (13) is dependent
upon the dihedral angle 9 between the C -X and C - H bonds (16),
16
determination of the effect of varying 9 in the reactant trans-l-bromo-2chlorocycloalkane was examined.
A variety of substrates with different
70
ranges of 9 were available by varying the ring size from 4 to 8
within the cycloalkyl series.
Previous work in the area of complex base-promoted elimina,
^
,.
,
tions 32,33,39,40 ^.
has also shown the preference for 3-halogen-activated syn elimination relative to unactivated anti elimination from
trans-1.2-dihalocycloalkane substrates (Equation 10). However,
B-Halogenactivated
\/Unact ivated
X
Anti
Elimination
H
>
H r/
^
(10)
Syn
Elimination H
H
H
H
a comparison of the relative rates of 6-halogen-activated anti and
syn elimination, induced by complex base, had not been previously
undertaken.
Comparison of these relative rates allows a determination
of the effect of the proposed special substrate-complex base interactions upon the ordinarily strong preference for anti elimination
2 12
which is generally seen in closely related elimination reactions. '
The determination of the k ^./k
ratios for eliminations from
anti syn
a series of 1,2-dichlorocycloalkanes was therefore pursued.
Lee and Bartsch's observations
39 40
'
that the normally poorer
Leaving group is preferentially removed from cyclohexyl and cyclopentyl
substrates requires further investigation.
As is shown in Equation 11,
the two competitive syn elimination processes differ not only in
leaving group, but also in the identity of the 6-halogen activating
71
-HX(6 to Y)
<
/
\ -HY(6 to X)
( X H )
> (
H
group,
)
(11)
Y
A competitive reaction technique, which was employed in the
present study, allows the cause for the observed loss of the normally
poorer leaving group to be apportioned between leaving group and
3-activating group effects. Thus, the mechanistic source for this
propensity for loss of the "poorer" leaving group can be better
understood.
In addition to examining the role of the leaving group and
3-activating group in the complex base promoted elimination reactions,
experiments designed to probe the effect of a-activating group identity,
and studies of dehydrohalogenations from substrates with non-halogen
3-activating groups were undertaken as a portion of this research.
Conclusions derived from the examination of the results are also
useful in rationalizing the unusual features of elimination induced
by complex base.
The remainder of this chapter is devoted to the detailed presentation of the results of the research which
focused on the areas
mentioned above, and to the discussion of the experimental results
within the context of the mechanism of 6-elimination induced by
complex base.
72
Nature of the Complex Base
Caubere and coworkers
37
have demonstrated that variation of
R in the complex bases NaNH2-NaOR has an effect upon the relative
proportions of debromination and dehydrobromination from trans1,2-dibromocyclohexane.
In light of the finding of Lee and Bartsch '
that the complex base NaNH2-NaO-t_-Bu induces preferential loss of
the normally poorer leaving group in 6-elimination from trans-1,2dihalocycloalkanes, a study of the effect of alkoxide component
variation in the complex base upon the competing dehydrohalogenations
of a mixed dihalide substrate was undertaken.
78
In this way, the
nature of the actual elimination-promoting species can be probed.
Thus, trans-1-bromo-2-chlorocyclohexane was treated with various
complex bases (Equation 12), employing the standard complex base
elimination procedure which is described in the Experimental Section.
NaNH -NaAnion
Br
H
•
(12)
+
>
THF, Room Temp.
H
CI
17
18
19
Results from the reactions of the substrate ] ^ with 27 combinations
12 3
of NaNH2-NaOCR R R are given in Table 3.
Substrate 1_7 was selected for this study based upon the fact
that both dehydrochlorination and dehydrobromination are observed
in the reaction of 17^ with NaNH2-NaO-_t-Bu in THF at room temperature
73
TABLE 3
Elimination Reactions of trans-l-Bromo-2-chlorocyclohexane Induced
12 3
by NaNH2-NaOCR R R in THF at Room Temperature
, J -,
For NaNH2-NaOCR R R
7
2
3
System
R
R^
R"*
Me
Time
Required
for
Consumption
of 17(h)
„-j,a
^°—
%18^ + %19^
(x 100)
Total
Yield b
18 + 19'
H
H
24
51
51
2
n-• ^ 5 ^ 1 1
H
H
24
37
8
3
n-
H
H
21
45
28
n-
H
H
28
62
70
5
n-
"^lA3
H
H
26
49
56
6
n"^17^35
H
H
21
54
41
7
s-Bu
H
H
1
60
59
8
2.-BU
H
H
1
60
84
9
t-Bu
H
H
1
64
71
10
Me
Me
H
1
60
64
11
Et
Me
H
1
55
52
12
n-Pr
Me
H
1
58
56
13
n.-Bu
Me
H
1
62
69
14
il-^6^13
Me
H
>1
62
28^
-S^5
•S»19
15
Et
Et
H
1
54
54
16
n-Pr
Et
H
1
60
56
17
j.-Pr
Me
H
2
61
56
18
s-Bu
Me
H
1
61
73
74
TABLE 3 (Continued)
12 2
For NaNH2-Na0CR R R-^
1
2
3
System
R
R
R
Time
Requ:
Required
for
Consumption
of 17(h)
a
'"'^~
^^^
%1^ + %1^
(x 100)
Total
Yield
18 + 19'
19
i.-Bu
Me
H
1
59
36
20
t-Bu
Me
H
1
65
83
21
-^4^8-
«
1
62
59
22
-^sHio-
H
1
54
68
23
Me
Me
Me
2
65
87
24
Me
Me
Me
0.5
3
76
25
Et
Me
Me
1
65
83
26
Et
Et
Me
2
63
80
27
CF^
H
H
1
59
79
28
CF^
CF^
H
>24
64
33^
Standard deviation of ±1% in repetitive analysis of reaction
mixture.
Standard deviation of ±2% from repetitive analysis
of a reaction mixture.
c
Reaction was incomplete. Product data
are after 1 h of reaction.
15-crown-5 was present in the reac-
tant ratio of j^7 :NaNH2-NaO-_t-Bu:15-crown-5 = 2:3:6.
was incomplete.
Reaction
Product data are after 24 h of reaction.
75
Therefore, small variations in the relative rates of competitive
dehydrohalogenations would be observable in reactions of 1_7' while
such changes might not be so readily evident if, for example,
_trans-l-chloro-2-fluorocyclohexane (which gives only dehydrochlorination upon reaction with NaNH2-NaO-t_-Bu) were used as a substrate in
this study of alkoxide component variation.
Table 3 lists the approximate time required for consumption of
l]_ (to <1% remaining), as well as the relative percentage of ] ^ in
the product mixture of 18 and j ^ , and the combined yield of 18^ and
19.
The influence of 15-crown-5 upon the competitive elimination
modes can be seen by comparing systems 23 and 24 (Table 3 ) .
A transition state (13) has been proposed for these complex
base-induced eliminations which involves an interaction of the
counterion of the base (Na ) and the leaving group.
If such inter-
actions are important, addition of a strong sodium ion complexing
agent should reduce or eliminate any interaction of Na
leaving group.
with the
A comparison of systems 23 and 24 (Table 3) shows
that the introduction of an equimolar (with Na ) quantity of 15crown-5 diminishes the proportion of dehydrochlorination from 65%
to 3%.
Thus in the presence of a Na
- selective ionophore, the
syn elimination exhibits the normal E2 propensity for loss of Br
over CI.
This observation argues strongly for a transition state
such as 1^ being operative in these reactions.
The standard complex base reaction procedure used in this study
(Experimental Section) employs a 50% excess of complex base.
Therefore,
control experiments were conducted with elimination products 18 and
76
19^ in order to determine if the products of elimination undergo
further reaction with complex base.
Treatment of ] ^ and j ^ according
to the procedure outlined for control experiments in the Experimental
Section, employing NaNH2-NaO-t^-Bu at room temperature for 24 hours,
caused partial decomposition of the product 1-halocyclohexenes to
unidentified products.
However, addition of finely ground NaCl
or NaBr diminished the decomposition of the 1-halocyclohexenes.
These results suggest that rapid (1-2 hr) reactions of lj_ with
complex base should produce colloidal NaBr and NaCl, which would
tend to deactivate the excess base and hinder further reaction
(decomposition) of the elimination products.
Comparison of the relative
percentage of 1^ and the total yields of 1^ and 1^ in the reaction
of L7 with NaNH2-NaO-t^-Bu after 2 hours (system 23, Table 3) and
after 24 hours
39
shows no appreciable difference.
This supports
the hypothesized deactivation of the remaining complex base by
colloidal product salts.
Slower reactions of 1_7^ with complex bases
may allow the product 1-halocyclohexenes to be subjected to the
active complex base for extended periods and product decomposition
may be significant.
A dependence of the time required for consumption of 17^ in
the standard reaction upon the structure of the alkoxide component
of the complex base can be readily seen upon examination of the data
in Table 3.
Reactions with alkoxide components derived from n_-alcohols
(systems 1-6, Table 3) were comparatively slow, and the reported
product data for these reactions may be unreliable due to the product
decomposition previously discussed-
Reactions using alkoxide components
77
derived
from branched primary Csystems 7-9, Table 3), secondary
(systems 10-22, Table 3), and tertiary alcohols (systems 23, 25, 26;
Table 3) were comparatively fast C<2 hours).
As discussed above,
product decomposition should be unimportant in these fast reactions.
Examination of the data for these reactions shows a general preference
for dehydrochlorination over dehydrobromination.
The relative per-
centages of j ^ are in the range of 54-65%. Values for the total
yield of 1^ and 1^ vary considerably with the choice of alkoxide
component in the complex base. Competing dehalogenation (to give
cyclohexene) is a major factor responsible for the less than quantitative yields of 2^ and _19^. Caubere and coworkers
37
have previously
demonstrated the sensitivity of competitive dehydrohalogenation vs.
dehalogenation to alkoxide component identity in the complex base.
The reactions which utilized complex bases prepared from tertiary
alcohols produced the highest yields of dehydrohalogenation products.
Reactions were conducted using complex bases with alkoxide
components derived from 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoropropanol (systems 27 and 28, Table 3; respectively) in order to
probe the role of electronic features of the alkoxide component of
the complex base upon the reaction.
Comparison of the results obtained
for the alkoxide of 2,2,2-trifluoroethanol (system 27, Table 3)
and for ethoxide (system 1, Table 3) shows that the former is much
more reactive. However, comparison of the reactions involving
l,l,l,3,3,3-hexafluoro-2-propoxide (system 28, Table 3) and its
non-fluorinated analog (system 10, Table 3) reveals that the reaction
involving the fluorinated base component is more sluggish than the
78
reaction utilizing the corresponding non-fluorinated alkoxide.
reasons for these conflicting reactivities are not known.
both perfluorinated
The
However,
systems (27 and 28, Table 3) show the same
preferential dehydrochlorination which was seen with other alkoxides.
Due to the heterogeneous nature of the complex base reaction
mixture, and the recent successful rate enhancements reported
87 88
*
for certain heterogeneous reaction systems when subjected to ultrasonic irradiation, reactions of r7 with complex base were conducted
under conditions of ultrasonic irradiation.
Thus, reactions of r7
with NaNH2-Na0-^-Bu in THF with no external heating were conducted
in an ultrasonic cleaning bath.
The observed modest reactivity
increases were found to be solely due to the heating (to '^40°C)
of the water in the cleaning bath during irradiation.
Thus, a
parallel reaction conducted at 40°C in the absence of ultrasonic
irradiation gave identical elimination product proportions, yields,
and time required for substrate consumption as those obtained with
ultrasonic irradiation.
Complex bases derived from sodium amide and non-alkoxide components were also employed in the elimination of ^Z (Equation 12).
Results obtained from the reaction of l^^ with eight combinations
of NaNH^-NaAnion (where Anion is not alkoxide) are reported in Table 4.
In addition to the alkoxide components employed in effective
complex bases (present study), phenoxide ions (systems 29-31, Table 4),
and an enolate system (system 34. Table 4) can also be employed as
effective base components.
However, carboxylate ions appear to be
poor complex base components (systems 32 and 33, Table 4 ) . KHiile
79
TABLE 4
Elimination Reactions of trans-l-Bromo-2-chlorocyclohexane Induced
by NaNH2-NaAnion
in THF at Room Temperature
Time
Required
for
Consumption
of 17(h)
7,ia
Total
Yield
System
Anion of
NaNH2~NaAnion
29
phenoxide
1
62
80
30
£-methoxyphenoxide
1
60
69
31
£-methoxyphenoxide
1
61
81
32
benzoate
>4
71
33
propanoate
>4
68
12^,c
34
enolate from
2-butanone
1
57
53
35
_t^-butylthiolate
2
62
89
36
thiocyanate
1
55
57
%18 + %19
(x 100)
18 + 19_m
4a,c
Standard deviation of ±1% in repetitive analysis of reaction mixture,
Standard deviation of ±2% from repetitive analysis of reaction
mixture.
^Reaction was incomplete.
cyclohexene were seen.
Some starting material and much
Product data are after 4 h of reaction.
80
the inorganic complex base combination of NaNH -NaSCN (system 36,
Table 4) appears to be an effective complex base, complex base
combinations of NaNH2-NaN02, NaNH2-KSCN, and NaNH2-NaCH2CN employed
under similar reaction conditions, gave less than 2% of elimination
from l]_ after 4 hours.
The complex base NaNH2-NaCHPhCN produced
40% of dehydrohalogenation products after the 4 hour (incomplete)
reaction in addition to several unidentified side products.
Examina-
tion of complex bases, prepared from NaN02, NaSCN, KSCN, NaCH2CN
and NaCHPhCN in this study, was prompted by the report
89
that such
sodium and potassium salts facilitate aryne reactions.
In an attempt to probe the possibility of one electron transfer
processes being important in this complex base reaction (a possibility
which must be considered in reactions employing strongly basic reagents
90 91
' ) , a complex base of NaNH2-NaS-_t-Bu was employed in the
elimination of rZ (system 35. Table 4).
Comparison of the results
obtained for reactions of 17^ with complex bases derived from t^-butoxide
and t_-butylthiolate (system 23, Table 3; system 35, Table 4; respectively) show essentially identical results.
Based upon this result,
one electron transfer processes are assumed unimportant in these
reactions.
Dehydrochlorination is the preferred mode of reaction for the
systems recorded in Table 4.
In fact, the constancy in the relative
proportions of j ^ and 1^ observed for reactions of l]_ with complex
bases derived from NaNH2 and a wide variety of other anionic components argues strongly that the role of the latter anionic components
is only to activate the surface of the NaNH2, which, apparently is
81
the active base component.
In summary, alkoxide complex base components with a certain
degree of hydrophobic bulk near the oxygen atom of the alkoxide
(all except those derived from n-alcohols), and some inorganic and
other oxyanionic components are effective activating agents for
the sodium amide in the complex base reagents.
Results of this
study of the nature of the complex base are consistent with a
transition state of type 12, in which the base B is the amide ion
(NH^ ) , and the base-counterion M is the sodium ion (Na ) . The
alkoxide (or related anionic) component of the complex base apparently
facilitates the reaction by activating the surface of the sodium
amide.
Effect of Ring Size Variation upon
Competitive Dehydrobromination and
Dehydrochlorination Promoted by
Complex Base and by t-BuOK-t-BuOH
A transition state l^. (where B is the amide ion and M is the
39 40
sodium ion) has been proposed
*
to explain the unique syn stereo-
chemistry and the surprising propensity for loss of the normally
poorer leaving group in complex base-promoted elimination from trans1J2-dihalocyclohexanes.
Since simultaneous interactions of both
the 6-hydrogen and the leaving group with the complex base are
postulated in this six-centered transition state, variations of
the dihedral angle 9 between the C -X and C^-H bonds (induced by
a
ts
ring size variation in the cycloalkyl substrates, 16) should influence
the reactions of trans-1,2-dihalocycloalkane substrates with complex
82
base.
A preliminary survey
'
has shown that the ratio of dehydro-
chlorination: dehydrobromination in NaNH2-NaO-_t-Bu induced elimination
from two trans-l-bromo-2-chlorocycloalkanes (C, and C_) decreases
6
5
from 1.8 to 1.3 in going from the cyclohexyl to the cyclopentyl
compound in the series.
In order to examine the role of the ring size of the cycloalkane substrate upon the competitive dehydrobromination and dehydrochlorination induced by complex base, a series of trans-l-bromo-2chlorocycloalkanes (20, n = 2-6) was
subjected to complex base
(Equation 13). Variation of the value for n in 20 allows eliminations
(13)
H
_20
li
H
12^
from substrates with several ranges of 9 (16).
Treatment of 2^ with NaNH2-Na0-_t-Bu in THF at room temperature
following the standard complex base elimination procedure (Experimental Section) and GLPC analysis was utilized to determine the
reactivity and products.
The approximate length of time required
for consumption of _20, the relative percentage of dehydrochlorination
product 21 in the total 1-halocycloalkenes ^
bined yields of ^
and ^ , and the com-
and _22^ are given in Table 5.
obtained from the reaction of the substrates ^
Parallel results
with the more tradi-
r
83
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84
tional syn elimination-inducing base-solvent system. t^-BuOK-t_-BuOH,
at 50** (Equation 13, applying the _t-BuOK-_t-BuOH elimination procedure
given in the Experimental Section) are also recorded in Table 5.
This study is the subject of a recent communication.^^
For the associated base-solvent systems of _t-BuOK-t_-BuOH, t_-BuOKbenzene and _t-BuOK-toluene, 6-elimination that proceeds with syn
2 12
stereochemistry has been reported. '
A six-centered transition
state 2J. (with B = _t-BuO~ and M = K ) has been proposed by Sicher
and others
29 92
'
to account for this observed facilitation of syn
elimination pathways.
Comparison of the transition states proposed
for complex base eliminations (]^, B = NH^~ and M = Na ) and for
eliminations induced by ion paired _t-BuOK (12, B = t^-BuO" and
M = K ) shows striking similarities.
In view of these similar transi-
tion states proposed for the two base systems, a direct experimental
comparison of elimination from common substrates induced by NaNH^NaO-_t-Bu and t_-BuOK-t_-BuOH is warranted.
Since the t_-BuONa of the
complex base serves only to activate the complex base, the two types
of reactions reflected in Table 5 utilize the same initial concentrations of effective base and substrate.
The results of the parallel reactions recorded in Table 5 reveal
large differences in reactivity and regioselectivity for the two
base-solvent systems.
Many days were required for complete consump-
tion of most substrates (2^) when they were subjected to t^-BuOK-t_BuOH at 50**.
On the other hand the complex base reactions at room
temperature were complete in one or two hours.
This reactivity
85
difference demonstrates the synthetic advantage of employing complex
base for inducing syn dehydrohalogenation from trans-1,2-dihalocycloalkanes as compared with more typical base-solvent systems.
Examination of the data in Table 5 shows that the ring size
of the trans-1-bromo-2-chlorocvcloalkane exerts a notable influence
upon reactivity in eliminations from 2^ induced by t^-BuOK-t^-BuOH
at 50°C.
While the cyclobutyl substrate required only one day for
completion of the reaction, the cyclooctyl system reaction was
observed to be complete only after 5 days.
The cyclopentyl, cyclo-
hexyl and cycloheptyl systems showed incomplete reaction (as demonstrated by the presence of varying amounts of substrates, and less
than quantitative product yields) even after five days of reaction.
Reactivity differences may be attributed to different elimination
dihedral angles (0, 2^) for the various substrates.
On the other
hand, only very small reactivity differences were seen with analogous
eliminations from 2^, induced by complex base at room temperature.
This variation in effect of ring size upon the reactions involving
79
the two base-solvent systems reflects
a difference in the transi-
tion states for the two reaction groups.
The amide ion, the highly
basic effective base in the complex base, should produce an Elcb-like
E2 transition state which has little double bond character.
This
is consistent with the insensitivity of reactivity to ring size
seen with complex base-induced dehydrohalogenation.
However, the
transition state for the elimination induced by t^-BuOK would be
expected to have a less carbanion-like transition state and more
86
double bond formation, as is indicated by the experimental results.
Comparison of competive dehydrobromination and dehydrochlorination induced by the two base-solvent systems is also instructive.
Reactions of 2^ with t^-BuOK-t_-BuOH at 50''C gave 83-95% of dehydrobromination (loss of -HBr preferred).
Enhanced proportions of
dehydrochlorination are seen in every case when complex base is
substituted for t^-BuOK-t^-BuOH.
Therefore, although transition
states (12 and ]^) which involve significant interactions of base
counterion and leaving group (X, M interaction in j ^ or 13) have
been proposed
12 29 39 40 92
' ^•»^^» '
for eliminations by
both complex base
and t_-BuOK-t_-BuOH, such interactions (which would favor preferential
removal of the normally poorer,
group)
'
but more electronegative leaving
appear to be stronger in the case of complex base-induced
elimination.
Examination of the competitive loss of HBr and HCl from 20 induced
by complex base shows that dehydrochlorination predominates (cyclobutyl
and cyclohexyl systems) or is essentially equal to (cyclopentyl and
cycloheptyl systems) dehydrobromination in most cases.
cyclooctyl case does dehydrobromination predominate.
Only in the
Perhaps this is
due to weakened base counterion-leaving group interactions which result from steric interactions between the complex base surface and
the cyclooctyl ring residue.
79
In summary, comparison of eliminations
from 20 (Equation 13) promoted by _t-BuOK-_t-BuOH or NaNH2-NaO-t^-Bu show
that the complex base reactions are more rapid, show less sensitivity
to substrate ring size, and demonstrate a greater tendency for dehydro-
87
c h l o r i n a t i o n t h a n do c o r r e s p o n d i n g r e a c t i o n s w i t h t_-BuOK-£-BuOH.
.
.
7Q
This is consistent with the proposal
that the complex base-promoted
eliminations have transition states with stronger base counterionleaving group interactions and more carbanion character and less
double bond development than the transition states for parallel
eliminations induced by the aggregate base t-BuOK.
Competitive Syn and Anti Dehydrochlorination Induced by Complex Base
As was discussed previously in this dissertation, the preference
for 6-halogen-activated syn elimination relative to unactivated
anti elimination from trans-1,2-dihalocycloalkanes, induced by
10
complex base, has been established by previous work
QQ
'
*30 / C\
' *
(Equation 10). Comparison of the relative rates of B-halogen activated syn and anti elimination induced by complex base, however, has
not been made.
Such a comparison allows the effect of the proposed
unique complex base-substrate interactions upon the normal strong
preference for anti elimination (generally seen for closely analogous
2 12
reactions ' ) to be assessed. Therefore, a series of experiments,
which are described below, were undertaken in order to determine the
effect of these proposed special complex base-substrate interactions
upon the ratio of 3-halogen activated anti and syn elimination.
Cristol's classic study
2ft
of elimination from the benzene
hexachloride isomers (1,2,3,4,5,6-hexachlorocyclohexane isomers)
has shown a strong preference for anti stereochemistry in dehydrochlorination (r^-chloro-activated) from these substituted cyclohexanes.
88
Comparison of the rates of reaction with base for a number of these
isomeric benzene hexachlorides showed a very strong preference for
anti dehydrochlorination.
For example, Cristol^^ found that 9
(which has all of its substituent chlorine atoms trans to each other
around the ring, and is only capable of syn dehydrochlorination)
H
/ci
H
CI
H\
CI
V CI
H
CI
H
reacted with base 7000-24,000 times slower than did the other
isomeric benzene hexachlorides, which had the possibility of at
least one anti dehydrochlorination pathway.
Thus, a very strong
preference for £-halogen activated anti elimination (compared to
3-halogen activated syn elimination) for these cyclohexyl systems
was demonstrated.
In order to assess the relative proportions of 6-halogen
activated anti and syn elimination, induced by complex base, competitive dehydrochlorination from cis- and trans-1,2-dichlorocycloalkanes
was studied (Figure 4).
Competitive reactions of cis- and trans-1,2-
dichlorocycloalkanes with complex base (employing the competitive
complex base elimination procedure given in the Experimental Section
89
(CH-) .
2 n
^^»2)n
CI
23
CI
CI
H
H
24
anti
(CH2)^
H
'CI
25
Figure 4.
6-Halogen Activated Syn and Anti Dehydrochlorination
of this work) and analysis (GLPC)of aliquots periodiocally removed
from the incomplete reaction mixture allowed calculation (Substrate
Method, Appendix) of the ratio of rate constants for the anti and
syn pathways.
Thus treatment of 2^ and _24_ (cyclopentyl to cyclooctyl
ring sizes) with NaNH -Na0-_t-Bu in THF at 20.0" (Equation 14)
H
(CH2)^
(CH2)„
(™2>n
NaNH2-Na0-_t-Bu
+
CI
CI
(14)
->
THF, 20.0°C
23
24
25
90
allowed the calculation of k^^^./k
for these reactions.
ant 1 syn
The
results for these competitive dehydrochlorinations, and for the
analogous complex base reactions with ^
and 2^ (Equation 14 and
Figure 4 with compound 26 substituted for 23, 27^ substituted for
_26^; X = H, Y = CI
27; X = CI, Y = H
24, and the appropriate dehydrochlorination product from 26 or 27
substituted for 25) are given in Table 6.
Examination of the data in Table 6 shows that dehydrochlorination
from substrate types 2_3 and 24^, induced by the complex base NaNH^NaO-t-Bu in THF at 20.0^0, gave much diminished values for k
./k
—
^
anti syn
when compared to the magnitude of these effects which are usually
encountered (7000-24,000 for k
./k
from Cristol's work
anti syn
discussed above).
2 fi
This effect is probably attributable to the
facilitation of the 6-chloro-activated syn pathway by the special
features of the complex base-substrate interactions discussed above.
For substrates 2^ and 21_^ syn elimination is seen to predominate
(Table 6). Preferential syn stereochemistry has also been noted
91
TABLE 6
Competitive 6-Halogen Activated Syn and Anti Dehydrochlorination
from 231 and 2A_, or 2^ and 27^ Induced by NaNH2-NaO-t_-Bu
in THF at 20.0°C
Identity
of trans-1,2Dichloride
Substrate
Identity
of cis-1,2Dichloride
Substrate
Ring Size
of Z3
and~24
k
k
^.a
anti
syn
22
24
5
1 5 . 0 ± 1.6^
±2
24_
6
10.2 ± 0 . 9
2_3
24
7
8.8
22
24_
8
36.5 ± 4.5
26
27
0.13
± 2.1
± 0.03
a Ratio of rate constants obtained for 4 analyses each of 2-5 reactions.
See text.
Standard deviations from analysis of 8-20 reaction samples.
92
by Cristol and Hause
27
for eliminations from 2^ and 2]_ induced by
sodium hydroxide in 50% dioxane-ethanol at 110°C.
The k
./k
anti
syn
value of 0.13 calculated by Cristol for the elimination induced by
hydroxide is identical with the value obtained with complex base
(Table 6 ) . It is possible that the benzene rings of substrates 2i
and 2Z. provide steric interference to the approach of substrate
to the activated complex base surface.
Therefore, in the dehydro-
chlorination of 26 or 11_, a transition state of type 12 (which
entails a six-centered transition state having important interactions
between the base counterion and the leaving group in addition to
the interaction of proton and base) may be precluded by the steric
requirements of the system.
Thus, the behavior observed with the
more traditional base (hydroxide) is mirrored in the reaction of
26 and 2T_ with complex base.
An effect of ring size upon the relative proportions of anti
and syn dehydrochlorination from the cis- and tran£-l,2-dichlorocycloalkanes (23 and 24) is evident from the results presented in
Table 6 for the cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl
systems.
As the ring size is increased from five through eight
the proportion of anti elimination appears to decrease modestly
and reach a minimum at the cycloheptyl ring size.
an abrupt increase for the cyclooctyl system.
There is then
The higher percentage
of anti elimination encountered in the cyclooctyl case may be due
to a poorer "fit" of substrate to the syn elimination-inducing
transition state 13, due possibly to an interfering
interaction
93
of the residue of the cyclooctyl ring with the complex base surface.
The premise that the syn-inducing transition state is less favored
in the cyclooctyl case than in the other systems of the series
reported in Table 6 is consistent with the somewhat anomalous
results obtained for the reaction of trans-l-bromo-2-chlorocyclooctane
with complex base (Table 5). In each of the analogous reactions of
trans^-l-bromo-2-chlorocycloalkanes (C,-C ) , dehydrochlorination was
preferred over or was essentially equal to dehydrobromination.
Only in the cyclooctyl case was loss of the normally poorer leaving
group (which has been attributed to the operation of the special
complex base transition state 13) not observed.
Thus, both the
special enhancement of the pathway giving syn stereochemistry and
the unique preference for loss of the normally poorer leaving group
usually seen with complex base are diminished in the case of elimination from 1,2-dihalocyclooctanes, relative to results obtained with
complex base for the homologous series of substrates.
A further experiment which is designed to assess the proportions
of .:-chloro-activated syn and anti dehydrochlorinations is represented
in Figure 5.
Due to the conformational flexibility exhibited by
the cyclododecyl ring system, products of both 6-chloro-activated
syn and anti dehydrochlorination can be produced from a single substrate (22 or 2 2 ) .
Treatment of 28^ or ^
with NaNH -NaO-^-Bu in THF at room tempera-
ture (according to the standard complex base elimination procedure
given in the Experimental Section, Equation 15), followed by GLPC
94
28; X = CI, Y = H
29; X = H, Y = CI
CI
H
X
I
\
CI
CI
(Z)
CE)
30
31
Figure 5. Competitive Syn and Anti Dehydrochlorination from cis- or
trans-1,2-Dichlorocyclododecane
(15)
+
>
^—^__>
1
CI
/
CI
CI
H
28; X = CI, Y = H
30
31
29; X = H, Y = CI
analysis of the product 1-chlorocyclododecenes, and determination
of the appropriate product ratio led to values for k
are recorded in Table 7.
^-/^
which
For the purpose of comparison, results
95
TABLE 7
Competitive Syn and Anti Dehydrochlorination from cis- or trans1,2-Dichlorocyclododecane Induced by NaNH2-NaO-_t-Bu in THF at
Room Temperature, or t-BuOK-t-BuOH at 50.0^0
Identity of
Substrate
Identity of
Base/Solvent^
anti
k
syn
28
A
25
29
A
18
28
B
38
a
A = NaNH -NaO-_t-Bu, B = t^-BuOK-t_-BuOH.
of ±
%.
b
Estimated uncertainty
96
for the reaction of 2^ with 0.5 M t-BuOK-_t-BuOH (following the elimination procedure described in the Experimental Section for t_-BuOK-t_BuOH) at 50**C are also listed in Table 7.
Comparison of the results obtained from the reactions of 28 and
22 with complex base and the reaction of 28^ with t^-BuOK-^-BuOH at
50°C demonstrates again the facilitation of syn elimination relative
to anti by complex base.
Even when compared with the
associated
12
base _t^-BuOK-t^-BuOH, which is known
to favor increased syn elimina-
tion, further enhancement of the syn reaction mode is observed with
complex base.
Evaluation of the results obtained when 2S^ is treated with
complex base, and the results obtained from the treatment of 22.
with complex base is more difficult.
The small variation in the values
of k
,/k
obtained for these two reactions, if not due entirely
anti syn
to experimental error, may be attributable to subtle differences
in the two reactions - possibly due to two different ranges of
conformational preferences which might be envisioned for the two
substrates 2§. ^^^
29.
In summary, experiments have demonstrated a marked facilitation
of the 6-halogen activated syn elimination pathway relative to the
3-halogen activated anti elimination pathway in complex base-induced
dehydrochlorinations of several 1,2-dichloro substrates, when the
results of these experiments are viewed in light of the great preference
for anti elimination which is generally seen with conventional bases.
The results of these experiments can be explained in terms of a
97
transition state for the syn pathway, which includes special interactions of the complex base surface with the leaving group.
The
postulated nature of the complex base (alkoxide-activated sodium
amide aggregates) produces the special facilitation of the syn
elimination pathway by allowing simultaneous interactions of baseproton and leaving group-base counterion.
Such a combination of
interactions (geometrically forbidden in the anti pathway) is
postulated to enhance the syn elimination pathway.
Leaving Group and 3-Activating
Group Effects
In the section of this chapter dealing with the effect of ring
size of the cycloalkane substrates upon the relative propensity for
dehydrochlorination vs. dehydrobromination from trans-l-bromo-2chlorocycloalkane substrates, induced by complex base, various factors
bearing possible influence upon the two competitive reaction pathways
were discussed.
An examination of the two possible route of dehydro-
halogenation available for a trans-1-bromo-2-chlorocycloalkane
substrate (Equation 16) reveals that the two different elimination
^ ""^ -HBr(3 to CI) /
<
h^
\
H
-HCKB to Br)
>
^
I
^ "^
1 (16)
98
pathways differ not only in the identity of the leaving group, but
also in the identity of the B-halogen group which activates the
6-proton.
Thus, comparison of the relative percentages of dehydro-
chlorination [-HC1(3 to Br)] vs. dehydrobromination [-HBr(6 to CI)]
from a trans-l-bromo-2-chlorocvcloalkane (Equation 16) involves
two mechanistic effects; those of the leaving group and the 8-activating group.
In order to more fully probe the nature of these two effects,
an experimental technique was employed in the present research
which allows the influence of each to be assessed independently
(Figure 6).
The competitive reaction of two elimination substrates
32 and 21 with base can theoretically give two dehydrohalogenation
products 2 ^ and 21 by three reaction pathways (Figure 6; X, Y =
halogens). Thus, 6-activated dehydrohalogenation from 22 ^^^ give 3^
[by the loss of HX(6 to Y)]and 22 [by the loss of HY(6 to X)],
while similar dehydrohalogenation from 21 gives only 22 [-HX(6 to X)].
With the assumption that the reaction of 22 ^i^h complex base gives
the same ratio of 34:22 in both the absence and the presence of the
second substrate, and applying a statistical correction factor for
the elimination from 22> these multiple reaction pathways may be
dissected to yield the leaving group effect and the 6-activating
group effect (as defined in Figure 6) for the system.
Competitive reactions (Equation 17) were performed for eleven
combinations of 21 and 32» using NaNH2-NaO-t_-Bu in THF at 20.0^0
(employing the Competitive Complex Base Elimination Procedure, given
99
(CH_)
2 n
H
(CH^)^.
Y
32
H
H
X
33
-HX(6 to Y)
-HY(6 to X)
-HX(6 to X)
i
V
(CH2),,
H'
X
<™2>n
Y
X
35
34
-HX(6 to X)
-HY(6 to X)
H
Leaving
Group
Effect
-HX(6 to X)
6-Activating
= Group
-HX(6 to Y)
Effect
Figure 6. Schematic Representation for the Possible Elimination
Pathways for Competitive Reaction of Two trans-1,2-Dihalocycloalkanes with Complex Base. The Leaving Group and 6-Activating
Group Effects are Defined in Terms of these Pathways.
in the Experimental Section).
The reactions involved the following
substrate combinations: four combinations (ring sizes C--Co) of transl-bromo-2-chlorocycloalkane and trans-1,2-dibromocycloalkane (Equation 17; X=Br, Y=C1, n=3-6); four combinations (ring sizes C^-Cg)
of trans-1-bromo-2-chlorocycloalkane and trans-1,2-dichlorocycloalkane
(Equation 17; X=C1, Y=Br, n=3-6); and three combinations (ring size
100
(CH,)^
X
H
(CH^)
NaNH ^ " \ NaO-E-Bu
+
X
H J
VTHF,
H
Y
32
H
(CH.) ,
2 n
(CH2)^,
>
(17)
20.0°C
X
33
34
35
C_-C^) of trans-l-chloro-2-fluorocycloalkane and trans-1,2-dichlorocycloalkane (Equation 17; X=C1, Y=F, n=3-5).
The inability to prepare
trans-l-chloro-2-fluorocyclooctane after repeated attempts precluded
the analogous reaction of the fluorochloride, trans-1,2-dichlorocyclooctane, and complex base. The leaving group effects and 6-activating group effects calculated for these systems (employing the Product
Method listed in the Appendix for all reaction systems except those
involving trans-l-chloro-2-fluorocycloalkanes, for which the Substrate
Method outlined in the Appendix was used) are listed in Tables 8 and 9,
respectively.
The heterogeneous conditions of complex base-promoted elimination
reactions preclude the determination of rate measurements for reactions
involving a single substrate. However, by conducting the competitive
reaction of two elimination substrates with the complex base, relative
reaction rates can be determined.
Thus, the leaving group and
3-activating group effects for eliminations from these trans-1,2dihalocycloalkanes, promoted by complex base have been determined.
101
TABLE 8
Leaving Group Effects for Eliminations from trans-1,2Dihalocycloalkanes Promoted by NaNH^-NaO-t^-Bu
in THF at 20.0°C
Leaving Group
Effect
Ring Size of trans-1,2-Dihalocycloalkanes
—
S
^6
S
S
-HBr(6 to Br)^
-HCl(6 to Br)
1.3 ± 0.4
1.1 ± 0.2
2.5 ± 0.2
2.7 ± 0.2
-HBr(6 to Cl)^
-HCl(6 to CI)
2.2 ± 0.7
1.9 ± 0.1
4.3 ± 0.9
5.9 ± 0.9
-HCl(6 to Cl)^
-HF (6 to CI)
0.91 ± 0.2
0.40 ± 0.1
0.32 ± 0.04
Obtained from the competitive reaction with complex base of trans1,2-dibromocycloalkane and trans-l-bromo-2-chlorocycloalkane (see
text for details).
Obtained from the competitive reaction with
complex base of trans-1,2-dichlorocycloalkane and trans-1-bromo2-chlorocycloalkane (see text for details).
Obtained from the com-
petitive reaction with complex base of trans-1,2-dichlorocycloalkane
and trans-l-chloro-2-fluorocycloalkane (see text for details).
102
TABLE 9
6-Activating Group Effects for Eliminations
from trans-1,2-Dihalocvcloalkanes Promoted
by NaNH2-NaO-_t-Bu in THF at 20.0°C
6-Activating
Group
Effect
Ring Size of trans-1,2-Dihalocycloalkanes
'8
-HBr(6 to Br)
-HBr(6 to CI)
1.7 ± 0.5
2.0 ± 0.3
2.1 ± 0.2
1.4 ± 0.1
-HCl(6 to Br)
-HCl(6 to CI)
2.8 ± 0.9
3.5 ± 0.3
3.6 ± 0.8
3.1 ± 0.5
Obtained from the competitive reaction with complex base of trans1,2-dibromocycloalkane and trans-l-bromo-2-chlorocycloalkane (see
text for details).
Obtained from the competitive reaction with
complex base of trans-1,2-dichlorocycloalkane and trans-1-bromo2-chlorocycloalkane (see text for details).
103
In order to properly interpret the results of the present study,
comparison of these results with analogous findings reported in the
literature for a related system is warranted.
Leaving group and
6-activating group effects for syn-exo eliminations from 2,3-dihalonorbornanes (26_; X,Y=halogen)
induced by sodium pentoxide in pentanol
at llO^C (which are reported in the literature
) are given in
Table 10.
36
Examination of Table 9 reveals that although the values for the
3-activating group effect in the complex base reactions contain
considerable uncertainty (which is attributable to the heterogeneous
nature of the reaction), there is little effect of ring size of the
cycloalkyl substrates upon the values for the S-activating group
effect for a given leaving group.
This is consistent with the
electronic nature of this effect.
A change in ring size would be
expected to have little influence on the ability of the halogen on
C
to acidify the proton on C .
6
•^
The data in Table 9 also demonstrate
B-activating group than CI.
Br to be a more efficient
This is consistent with the ordering
of ease of base-catalyzed carbanion formation from haloforms
104
TABLE 10
Leaving Group and 6-Activating Group Effects for Syn-Exo
Eliminations from 2,3-Dihalonorbornanes Promoted
by Sodium Pentoxide in Pentanol at llO^C 97
Leaving
Group
Effect
Value
-HBr(6 to Br)
-HCKB to Br)
24
-HBr(p to CI)
-HC1(6 to CI)
15
6-Activating
Group
Effect
-HBr(6 t o Br)
-HBr(6 t o CI)
-HCl(6 t o Br)
-HC1(6 to CI)
Value
3.5
2.2
105
(CHBr^>CHBr2Cl>CHBrCl2>CHCl3) reported by Hine.^^ Hine^^ found
that substituent halogens, a to the extracted proton, exhibit facilitation of carbanion formation in the order I'\^Br>Cl>F.
A precise comparison of CI and F as 6-activating groups is not
possible with the data available in the current study.
Due to the
lack of dehydrochlorination [-HC1(6 to F)] from the trans-1-chloro2-fluorocycloalkanes (C^-C ) used in this study (no detectable 1fluorocycloalkene was observed as a product of these competitive
reactions), the calculated 6-activating group effects -HC1(6 to CI)/
-HCl(6 to F) would have to be very large.
Thus, the present results
seem to indicate that CI is a much more effective 6-activating
group than F.
This interpretation of the results is complicated
by the fact that the base counterion-leaving group interactions
suggested for the complex base transition state 22 ^^y ^^ very
strong for F, thereby reducing its activating ability and limiting
its role to that of a leaving group.
Therefore, the results may be
not so suggestive of the fact that fluorine is a very poor 6-activating
group, as being indicative that fluorine is an excellent leaving
group under complex base conditions.
The values of the 6-activating group effects for both the complex
base reactions (Table 9) and the eliminations from 32 (Table 10)
are of comparable magnitude.
reported
97
The eliminations from 2^^ have been
to proceed via a carbanionic E2 mechanism.
Therefore,
it seems reasonable to propose (based upon the comparable magnitudes
of the 6-activating group effects for both systems) that the complex
106
base eliminations possess transition states with similar carbanion
character.
Comparison of the change in magnitude of the 6-activating
group effect for the two base-solvent systems upon going from dehydrobromination to dehydrochlorination is instructive.
While the value
for the effect decreases upon going from dehydrobromination to dehydrobromination to dehydrochlorination for the norbornane systems, the
complex base systems exhibit an increase in the value of the 6-activating group effect for the same variation.
The results for the com-
plex base-induced eliminations are consistent with the tenents of
the Variable E2 Transition State Theory, which predicts that a change
to a poorer leaving group (Br to CI) would increase the carbanionic
2 10 12
in the transition state. ' *
character at C
p
Comparison of the magnitudes of the leaving group effects for
the complex base-promoted eliminations (Table 8) and the eliminations
from the norbornyl derivatives (Table 10) reveal that the leaving
group effects are significantly smaller for the former.
The leaving
group effects for the norbornyl system (Table 10) suggest transition
states with limited C -leaving group bond rupture.
Thus, while the
much smaller leaving group effects noted with com.plex base might be
thought to suggest an ElcB process (complete C - H bond rupture prior
to C -X bond rupture), these small leaving group effects may still
a
be consistent with an E2 mechanism.
The proposed transition state
for the complex base-induced eliminations 2Z involves significant
interactions between the sodium cation and the leaving group X.
In 37, the stronger leaving group-metal ion interactions for chloride
107
C
/' 6
c —
/
/
\
\
NH^
Na
37
than for bromide could partially offset the increased strength of
the C -X bond as a CI replaces Br as leaving group (X). In the
case of fluoride compared to chloride as the leaving group, the much
stronger fluoride-sodium ion interaction
appears to completely
offset the increased strength of the C -X bond as F reolaces CI as
a
leaving group (X). In this case, the Na-F interaction becomes
dominant, resulting in the leaving group effects of less than unity.
As would be expected from the nature of the transition state,
ring size variation (and the accompanying H-C -C -X dihedral angle
"
p
ot
variations) in the substrates induces notable changes in the values
of the leaving group effects (Table 8).
The larger leaving group
effects seen with the cyclooctyl systems compared to the cyclopentyl
or cyclohexyl systems (more correctly the smaller moderation of the
"normal" leaving group effect by a diminished partial offset of the
C -X bond strength by poorer X-Na
a
interactions) can be attributed to
108
a poorer accommodation of the required transition state geometry by
the cyclooctyl substrates, as has been suggested by other experiments
in the present research (vide supra).
Perhaps the source of this
effect is the steric hindrance to approach of the complex base by
the cyclooctyl substrate which arises from the interaction of the
residual methylene units of the cyclooctyl ring with the complex base.
In summary, the observed leaving group and 6-activating group
effects, observed with these complex base-induced dehydrohalogenations
from trans-1,2-dihalocycloalkanes, are consistent with transition
state 2Z. (which involves the special base counterion-leaving group
interaction).
The 6-activating group effect is virtually constant
with ring size variation of the cycloalkyl substrates. Therefore,
the varying tendencies for loss of the normally poorer leaving group,
which are observed with ring size variation, appear to be due to a
leaving group effect, rather than a 6-activating group effect.
g-Activating Group Effects
In addition to the effects of substituents at the 6 carbon
of the elimination substrate, the effects of substituents at the
a carbon can also yield valuable mechanistic information.
In order
to obtain some information about the effect of a substituent identity
upon the course of complex base reactions, two experiments were designed
and undertaken.
below.
The results of these two experiments are presented
109
2,3-Dichlorotetrahydropyran provides two possible 6-chloroactivated syn dehydrochlorination pathways (Equation 18). Elimina-
0
+ (
Cl
39
0
Cl
(18)
H
40
tion of the proton on the carbon adjacent to oxygen, together with
the appropriate Cl leaving group, gives 22» while elimination of the
other HCl pair leads to formation of 42*
In the case of the former
pathway (to give 39), the proton removed in dehydrochlorination is
activated by both the geminal chlorine atom and the geminal ring
oxygen.
In the latter pathway, the proton removed in dehydrochlori-
nation is activated by the geminal chlorine only.
In order to assess the effect of complex base upon the elimination substrate, 38^ was prepared and treated with NaNH2-NaO-t_-Bu in
THF at room temperature (employing the standard complex base elimination procedure found in the Experimental Section).
no starting material remained.
of 40, and no detectable 22*
After 6 hours,
GLPC analysis gave a 15.1% yield
Therefore, the products 22 ^^^ it^
were assumed to be unstable to the complex base, and undergo further
reactions to give unidentified product(s).
A parallel reaction of
38 with 0.5 M t-Bu0K-_t-Bu0H (50**, 24 hours; employing the elimination
110
procedure for _t-Bu0K-2-Bu0H given in the Experimental Section)
gave a 66% yield of 4^, and no detectable 39^.
Unfortunately, due to the product instability problems, meaningful
conclusions (based on these experiments) about the effect of substitution at the a carbon of the elimination substrate could not be
drawn.
In a further attempt to assess the effect of a substituent
at the a carbon of the elimination substrate, a competitive reaction
of (E)-l,2-dichloro-l-methylcyclohexane and trans-1,2-dichlorocyclohexane was undertaken (Equation 19).
While the kinetics of complex
NaNH2-Na0-2-Bu
(19)
+
>
THF, 20.0 C
Me
Cl
43
Cl
44
base reactions would be difficult to determine using single substrate
reactions, the use of competitive reactions to ascertain relative
reaction rates has been employed successfully in the present study
(vide supra).
Thus, a mixture of 41 (which gives ^
as the product of syn
B-chloro-activated dehydrochlorination) and 42 (which gives 44 as
its analogous elimination product) were treated with NaNH2-Na0-2-Bu
in THF at 20.0°C (in accord with the competitive complex base
Ill
elimination procedure given in the Experimental Section). Subsequent treatment of the raw data (Substrate Method, Appendix) and
application of a statistical factor allowed the effect of the
a-substituent to be assessed (Equation 20).
-HCl(6 to Cl, a to H)
= 5.8 ± 1.8
(20)
-HCl(6 to Cl, a to Me)
In the E2 transition state proposed for the syn 6-chloroactivated dehydrochlorinations (from substrates like 42 and 42)
induced by complex base (37, vide supra) the C-H bond-breaking
process has proceeded significantly, thereby inducing a carbanionic
character upon C^ (an ElcB-like E2 transition state).
If C^-X bond
scission has progressed significantly in the transition state, replacement by a methyl group (electron donating group) of a hydrogen on
the a carbon might stabilize the incipient positive charge at C^
in the transition state relative to the unsubstituted case, thus
producing a rate enhancement.
However, replacement by Me of H at C
is observed to produce
a small decrease in reaction rate (Equation 20).
This result is
consistent with a transition state which has much carbanion character
at C
(due to significant C--H bond breakage in the transition state)
S
^
and little or no carbocation character at C^ (due to little C^-X
bond rupture in the transition state).
The small rate decrease is
perhaps attributable to the destabilization (by the methyl group
on C ) of the negative charge at C . This long distance effect
could conceivably lead to decreases in rate of the magnitude observed
in the present case.
112
In making conclusions based upon the experiment illustrated
in Equation 19, one caution should be noted.
While 42 should prefer
a conformation with both chlorine atoms assuming equatorial positions,
43 may (due to the additional methyl group) not exhibit the same
conformational preference as 42* No attempt to correct for this
possible complication was made in calculating the a-activating group
effect (Equation 20).
In conclusion, examination of the role of a-activating group
effects suggests that dehydrochlorination from these trans-1,2-dihalocycloalkane substrates proceeds via a transition state with significant carbanion character at C^, and little or no carbocation character
p
at C , which is consistent with the results of the experiments disa
cussed earlier in this chapter.
Elimination from Substrates with
Non-halogen 6-Activating Groups
, , ,
• .
*. study
*• A
Investigations 32,33,39,40 undertaken
prior
to .u
the present
have shown that 6-halogen-activated syn dehydrohalogenation is
overwhelmingly preferred to unactivated anti dehydrohalogenation
in complex base-promoted eliminations from a number of trans-1,2dihalocycloalkanes (Equation 21; X=R=halogen).
(CH.).
2 "\
UnH/-(C«2^\ '- .
,
activated /
""X Activated
H ]<
k X
Anti
H\
Elimination ^
H
/
^
f/^'"2^n
/
> I
Syn
Elimination H
) (21)
R
113
However, in a preliminary investigation Lee^^ found that when
.tr^is-l-bromo-2-methoxycyclohexane was treated with NaNH2-NaO-_t-Bu
in THF at 22.5** for 24 hours both the product of unactivated anti
dehydrobromination (57%) and the product of B-methoxy-activated
syn dehydrobromination (9%) were detected (Equation 21; X=Br, R=OMe,
^•3).
A parallel reaction of trans-l-bromo-2-methoxycyclohexane
with _t-BuOK-_t-BuOH (0.6 M, 60*C for 24 hours) gave only 3-methoxycyclohexene, the product of the unactivated anti elimination.
Thus, elimination from this methoxy bromide with a non-halogen
B-activating group does not lead to exclusive 6-activated syn dehydro40
halogen upon reaction with complex base, but exhibits mostly
unactivated anti elimination.
The parallel reaction with the more
traditional base-solvent pair of jt-BuOK-_t-BuOH gave only unactivated
anti elimination.
In order to discover the generality of this phenomena, and to
examine the influence of such factors as leaving group identity,
B-activating group identify, and ring size upon the relative proportions of unactivated anti elimination vs. non-halogen B-activated
syn elimination, several substrates of type 42 (where X = halogen
and R = methoxy, tosyloxy, trimethylsilyloxy, or other non-halogen
B-activating groups) were treated with complex base. Thus, substrates
45 were treated with NaNH2-NaO-^-Bu in THF at room
temperature
and/or 50''C according to the standard complex base elimination procedure given in the Experimental Section (Equation 22).
of these
experiments are given in Table 11.
The results
114
TABLE 11
Dehydrohalogenations from Elimination Substrates
Containing Non-halogen 6-Activating Groups,
Induced by NaNH2-NaO-2-Bu in THF
System
Number
Substrate A5. Reaction
X
R
n Tempierature(°C)
37
Br
OMe
3
r. t.
38
Br
OMe
3
50°
39
Cl
OMe
3
r.t.
40
Cl
OMe
3
41
F
OMe
42
Cl
43
%Yield
Reaction %47^
Time (hr) %46 + %47 46 + 42^
(x 100)
24
18
90
5
58
91
144
81
33^
50°
5
91
77
3
50°
120
100
OMe
2
50°
1
19
92
Cl
OMe
4
50°
1
70^
51^
44
Cl
OTs
3
r. t.
24
0
0^
45
Cl
OTMS
3
r.t.
1
0
0^
46
Cl
SPh
3
r.t.
2
94
93
47
Cl
S02Ph
3
r.t.
100
93
^Estimated uncertainty of ±2%.
0.25
9^
Reaction was not complete - 44%
of the starting material remained.
Reaction was not complete -
91% of the starting material remained.
After '\'20% reaction
(15 minutes of reaction) the ratio of _46:47 was 12:88.
hexene oxide was recovered as the major product.
Cyclo-
115
H , (CH^ ,
(C«2>nX
->
X
H
H
V^'^2)n
(22)
+
H
H
45
47
46
Three substrates of type 42 were also treated with 0.5 M ;t-BuOK2-BuOH for 24 hours at 50.0°C (according to the elimination procedure
for 2~Bu0K-2-Bu0H given in the Experimental Section).
The results
of these reactions are recorded in Table 12.
In Tables 11 and 12 the reaction temperature, the approximate
time required for substrate consumption, the percentage of the product
of 6-activated syn elimination compared to the total of both syn
and anti pathways (Equation 21), and the total yield of both elimination products are listed for each reaction.
Attention should be
restricted to large differences in the product proportion and yield
data given in Table 11, since a control experiment has shown that
prolonged exposure of the product methoxycyclohexenes to complex
base at 50°C induces further reaction to unidentified products.
Siinilar decomposition may take place ^^ith the other elimination
products 46 and 47.
This makes the interpretation of small differences
hazardous.
iiiiiirf'r
116
TABLE 12
Dehydrohalogenations from Elimination Substrates
Containing Non-halogen 6-Activating Groups,
Induced by 2-BuOK-_t-BuOH at 50.0°C
System
Number
Substrate 45
X
R
n
48
Br
OMe
3
24
49
Cl
OMe
3
24
50
Cl
OTMS
3
24
Reaction
Time (hr)
a
0
c
_d
%Yield
46 + 47
21"
0"=
0<^
„
Reaction was not complete - 78%
of the starting material remained.
remained.
%46 + %47
(x 100)
b
Estimated uncertainty of ±2%.
detected.
%42^
No elimination products were
GLPC analysis showed 89% of the starting material
No elimination products were detected.
Only cyclo-
hexene oxide and starting material were detected by GLPC.
117
Comparison of the results obtained from the reaction of transl-bromo-2-methoxycyclohexane and trans-l-chloro-2-methoxvcyclohexane
at 50° with complex base (Table 11; systems 38 and 40, respectively)
and with ^-BuOK-^-BuOH (Table 12; systems 48 and 49, respectively)
reveals large differences in selectivity and reactivity for the
two base-solvent systems.
While the complex base reactions were
complete after 5 hours, the 2-BuOK-_t-BuOH reactions were incomplete
(only 21% of reaction was seen for the methoxy bromide, no elimination was seen for the methoxy chloride) after 24 hours of reaction.
With 2~BuOK-2-BuOH no syn elimination product 42 was observed in
the reaction of the methoxy bromide (system 48).
Reaction of the
same substrate with complex base showed 58% of the elimination proceeded by the syn pathway.
This enhancement of the syn pathway by
the employment of complex base is what would be predicted, considering
the special sodium ion - leaving group interactions in the transition
state proposed (vide supra) for these complex base reactions.
Complex base reactions were performed at both 50^0 and room
temperature for trans-l-bromo-2-methoxycyclohexane and trans-1chloro-2-methoxycyclohexane (Table 11; systems 37, 38 and 39, 40).
With the methoxy bromide, the increase in reaction temperature gave
an unexpected shift in selectivity, as well as the anticipated
increase in reactivity (compare systems 37 and 38). A parallel
selectivity shift is not seen with the analogous methoxy chloride
(compare systems 39 and 40), and the source of temperature dependence
of the selectivity in the case of the methoxy bromide is unknown.
118
The effect of leaving group identity upon the relative percentages of syn and anti elimination can be assessed for trans-1-halo2-methoxycyclohexanes in reaction with complex base at 50.0°C, by
comparing systems 38, 40, and 41 (Table 11). Replacing the bromo
leaving group with chloro, then fluoro, leads to increasingly higher
proportions of syn elimination.
Element Effect
41
This is consistent with Bunnett's
which would predict slower anti elimination as the
bromo leaving group was replaced with successively poorer leaving
groups (chloro, then fluoro), and the observation that complex base
exhibits normal leaving group "element effects" in anti eliminations.
39 40
'
For the syn elimination, induced by complex base, a
reversal of the normal leaving group ordering usually observed
for base-promoted dehydrohalogenations has been observed.
*
39 40
*
Thus, replacement of the leaving group bromo with chloro, then
fluoro would be expected to retard the anti pathway, while enhancing
the syn pathway.
This prediction is validated by experiment (compare
systems 38, 40, and 41).
Comparison of the effect of ring size upon the relative percentage
of 6-activated syn and unactivated anti dehydrochlorination, induced
by complex base at 50°C, (Equation 21) for three trans-l-chloro-2methoxycycycloalkanes is provided by systems 42, 40, and 43 (Table 11).
While the complex base reaction of the cyclopentyl homolog gives
mostly unactivated anti elimination (system 42), analogous reactions
of the cyclohexyl and cycloheptyl homologs give preferential reaction
via the B-activated syn pathway.
The reasons for this abrupt selec-
tivity difference remains unknown.
i:f,,-vv
-v__... ->
-Tl^*3I^WI51B
In addition to the trans-l-halo-2-methoxycycloalkanes discussed
to this point, substrates with other non-halogen 6-activating groups
were also studied (Equation 22; X = halogen, R ^ halogen or methoxy).
The reactions of trans-l-chloro-2-tosvloxvcvclohexane and trans[ (2-chlorocyclohexyl)oxy]trimethylsilane with complex base at room
temperature (systems 44 and 45) did not give dehydrochlorination,
but followed a substitution pathway to give cyclohexene oxide among
other products. Reaction of the silyl substrate with 0.5 M ^-BuOK-
2-BuOH at 50.0°C (system 50) gave only removal of the silyl protectir
group, analogous to the reaction with complex base.
The generality of this reaction for the removal of a trimethylsi
group
by
complex
base
was
demonstrated by the reaction of cyclo-
hexyltrimethylsilane with the base-solvent system.
The reaction
of the silane with NaNH^-NaO-^-Bu in THF at room temperature gave
cyclohexanol as the major product. An analogous reaction of the same
silane with 0.5 M ^-BuOK-^-BuOH at 50°C for 24 hours gave mostly
unreacted starting material and only '^^3% of cyclohexanol.
trans-2-Chloro-l-cyclohexyl phenyl sulfide, and the correspondii
sulfone were also treated with complex base at room temperature
(Table 11, systems 46 and 47). In both cases 6-activated syn dehydro
chlorination predominated (94% for the sulfide and 100% for the sulfc
The almost instantaneous reaction seen with the sulfone, and its
overwhelming preference for 6-activated syn elimination testify for
the high acidity of the 6-activated proton.
In summary, eliminations from substrates of type 45 (which
contain non-halogen 6-activating groups) generally react with comply
base to give enhanced B-activated syn dehydrohalogenation
relative
to unactivated anti dehydrohalogenation, when compared to analogous
reactions with _t-Bu0K-2-Bu0H.
This effect can be explained in terms
of a transition state for the complex base-promoted reactions, whicl
involves leaving group-base counterion interactions (37, vide supra)
Ring size, leaving group identity, and 6-activating group identity
have significant influence upon the relative propensities for unacti
vated anti elimination and 6-activated syn elimination (Equation 21)
CHAPTER IV
CONCLUSION
The experiments of this study have provided additional insight
into the mechanism of complex base-promoted 1,2-elimination reactions
Various features of these reactions have been probed.
The results of this study are consistent with the six-centered
transition state 2Z. ^^^^^ ^^^ been proposed
*
for these reactions.
Many of the unique features of these elimination reactions can be
explained in terms of the special base counterion - leaving group
interactions which are inherent in the proposed transition state 37.
Variation of the oxyanionic component of the complex base led
to the identification of the amide ion as the active base species
in these reactions. The oxyanionic component of the complex base
serves to activate the surface of the sodium amide aggregate, thus
facilitating reaction.
The variation of the ring size of the trans-1,2-dihalocycloalkyl
elimination substrates produces notable variations in the leaving
group ordering for these reactions.
Investigations which assessed
the effects of leaving group and 6-activating group variations for
these reactions allowed the source of this unusual propensity for
loss of the normally poorer leaving group (which is seen with certain
ring sizes) to be identified as an effect of leaving group.
Such
an effect would be expected, based upon the leaving group - base
counterion interaction proposed for the transition state of these
reactions.
121
HI
The facilitation of B-halogen-activated syn elimination relative
to 6-halogen-activated anti elimination as induced by complex base
was shown to be much greater than the facilitation provided by more
typical base-solvent systems.
In addition
compared with 2~Bu0K-
2-BuOH, complex base exhibited a greater propensity for 6-activated
syn dehydrohalogenation relative to unactivated anti addition for
elimination from substrates with non-halogen 6-activating groups.
The research reported in this dissertation has not examined
all of the possible features of these reactions. Therefore
further
work in the area of complex base-induced elimination is warranted.
Additional research could be focused upon the synthetic applications
of this elimination-inducing reagent, which were largely ignored
in the present work.
While the elimination substrates employed in
this research were cyclic compounds, elimination from acyclic substrates induced by complex base should also provide interesting
insight.
Very little attention was paid in the present study to the
effect of temperature upon these reactions. However in the case
of the complex base-promoted dehydrobromination of trans-l-bromo-2methoxycyclohexane, the reaction temperature had a marked effect
upon the relative proportions of 6-activated syn elimination and
unactivated anti elimination (vide supra).
Thus, the reaction tem-
perature may have a significant influence on other complex base
reactions.
While certain aspects of complex base-promoted eliminations
remain unknown, significant progress has been made in understanding
the complex features of this heterogeneous reagent.
LIST OF REFERENCES
Hofmann, A. W,
2.
Saunders, W. H., Jr.; Cockerill, A. F. "Mechanisms of Elimination Reactions"; Wiley-Interscience: New York, 1973; Chapters
1-4.
3.
Hanhart, W.; Ingold, C. K. 2- Chem. Soc. }^^y
4.
Hughes, E. D.
5.
Hughes, E. D.; Ingold, C. K.; Patel, C. S. 2- Chem. Soc.
^m-
Ann. Chem.
)^^>
1.
Z§.» ^53.
2- Am. Chem. 2o£«
997.
/t^» AZ.» ^O^.
526.
6.
Bordwell, F. G.; Knipe, A. C. ; Yee, K. C. 2* ^ * Chem. Soc.
1970, 92, 5945.
7.
Rappoport, Z.; Shohamy, E.
8.
Cram, D. J.; Greene, F. D.; DePuy, C. H. 2- ^ * Chem. Soc.
1956, 78, 790.
9.
Saunders, W. H., Jr.; Asperger, S.
79, 1612.
J. Chem. Soc. 2 1971, 2060.
J. Am. Chem. Soc. 1957,
10.
Bunnett, J. F. Angew. Chem. Int. Ed. Engl. 1962, 1, 225.
11.
More O'Ferrall, R. A.
'
J. Chem. Soc. B 1970, 274.
—
—
'\/\A/\j
Chem. Rev. \^^,
12.
Bartsch, R. A.; Zavada, J.
13.
Hammond, G. S.
14.
Swain, C. G. ; Thornton, E. R.
817.
J. M . Chem. 2o£-
15.
Gandler, J. R. ; Jencks, W. P.
1937.
J. Am. Chem. 22£- l ^ h
16.
Hammett, L. P. "Physical Organic Chemistry"; McGraw-Hill:
New York, 1940; Chapter 7; (2nd ed., New York, 1970; Chapter 11),
17.
Biale, G. : Cook. D.; Lloyd. D. J.; Parker, A. J.; Stevens,
I. D. R.; Takahashi, J.; Winstein, S. J. Am. Chem. Soc. 1971,
23, 4735.
18.
Bartsch, R. A.; Bunnett, J. F.
408.
J. Am. Chem. So£. \^^,
123
2^, ^53.
JJ_, 334.
J. Am. Chem. Soc.
\^?i^
84,
1^'
1^68, 90,
19.
Bunnett, J. F. In "Survey of Progress in Chemistry"; Scott,
A. F., Ed.; Academic Press: New York, 1969; Vol. 5, pp 53 - 93.
20.
Bartsch, R. A.; Croft, A, P. 2- 9lM.' Chem.
21.
Bartsch, R. A.; Read, R. A.; Larson, D. T.; Roberts, D. K.;
Scott, K. J.; Cho, B. R. 2* i^' Chem. Soc. /^^J^, 101, 1176.
22.
Br^zJnsted, J. N.; Pedersen, K. J.
23.
Caldin, E. F.
24.
Koch, H. F.; McLennan, D, J.: Koch, J. G.; Tumas, W.; Dobson,
B.; Koch, N. H. 2- ^ ' Chem. Soc. ^^^^, 105, 1930.
25.
Klyne, W. ; Prelog, V. Exp. , J ^ , 16, 521.
26.
Cristol, S. J.; Hause, N. L.; Meek, J. S. 2* ^*
11.
Cristol, S. J.; Hause, N. L. 2* j^* Chem. Soc. )^^y
2193.
28.
Zavada, J.; Svoboda, M.; Pankova, M. Tetrahedron Lett. /JJ?7i^>
711.
29.
Sicher, J. Angew. Chem. Int. £2- Engl, ^^J^* 2i» 200.
30.
Hofmann, A. W.
31.
Saytzev, A.
32.
Caubere, P. Ace. Chem. Res. , } ^ , ]_, 301.
33.
Caubere, P. "Topics in Current Chemistry"; Springer-Verlag:
New York, 1978; Vol. 73, pp 49-124.
34.
Caubere, P.; Coudert, G. 2* Chem. Soc., Chem. Commun. }^2^y
1289.
35.
Goering, H. L. ; Epsy, H. H. 2- ^ '
36
Guillaumet, G.; Lemmel, V.; Coudert, C ; Caubere, P. Tetrahedron
l^m30. 1289.
37.
Ndebeka, G.; Raynal, S.; Caubere, P.; Bartsch, R. A. 2- 0^8Chem, 1980, 45, 5394.
38.
Bartsch, R. A.; Lee, J. G.
Chem. Rev,
Ann. Chem.
Ann. Chem.
^^^y
;\^,
2* Phys. Chem.
42, 1364.
^ ^ ,
208, 185
22» l^^.
Chem. Soc.
74,
^ ^ , 22.* H -
^^J^,
119_, 296.
Chem. Soc. ^ ^ , 2^» 1454,
unpublished results.
1
39.
Lee, J. G.; Bartsch, R. A. 2- Am, Chem, Soc. ; j ^ , 101, 228.
^0.
Lee, J. G,
^1.
Bunnett, J. F.; Garbish, E. W., Jr.; Pruitt, K. M.
Soc. ^ ^ , 79, 385.
42.
Weinstock, J.; Lewis, S. N.; Bordwell, F. G. 2* ^ '
^m^
28, 6072.
43.
Carroll, B.; Kubler, D. G.; Davis, H. W.; Whaley, A. M.
Chem. Soc. ^^y
2A» ^382,
44.
Henniger, P. W.; Wapenaar, E.; Havinga, E, Rec. Trav, Chim.
\m>
81, 1053,
Doctoral Dissertation, Texas Tech University, 1978,
45. Nozaki, H.; Noyori, R. 2- 9l3.'
Chem, ^\^^y
Helv. Chim, Acta
2- ^ '
Chem.
Chem. Soc.
J, Am,
20, 1652.
^^^.
^y
46.
Prelog, V.; Speck, M.
1786.
47.
Heisig, G. B. 2- ^ '
48.
Clarke, H, T.; Gillespie, H, B,; Weisshaus, S. Z. 2* Am,
Chem. Soc. ^^^^y 2^, ^571,
49.
Roberts, J. D.; Sauer, C. W. 2- ^ -
50.
Weinstock, J.; Boekelheide, V. 2* Am. Chem. Soc. ^^^y
2546.
51.
Wittig, G.; Mayer, W. Chem, Ber.
52.
Zefirov, N. S.; Samoshin, V. V,; Subbotin, 0. A.; Baranenkov,
V. I.; Wolfe, S. Tetrahedron 1978, 2^, 2953.
53.
Isaacs, N. S.; Kirkpatrick, D,
54.
Croft, A. P.; Bartsch, R. A. 2* Org. Chem,
55.
Ashton, D. S,; Tedder, J, M,; Walton, J. C. 2- Chromatogr.
1971, 55, 231.
56.
Braude, E, A.; Forbes, W, F.; Gofton, B. F.; Houghton, R, P,;
Waight, E. S, J. Chem, Soc, 1957, 4711.
57.
Ziegenbein, W.; Hornung, K. -H.
58
Caubere, P.; Coudert, G.
59.
Croft, A. P.; Bartsch, R, A.
Chem. Soc. \^J*^y 21' 1^98.
Chem. Soc. ^^J*^y Jly
3925.
75,
I j ^ , 22, 329.
Tetrahedron Lett.
Chem. Ber.
1972, 3869
(in press).
1962, 21* 2976.
Bull. Soc. Chim. Fr.
1973, 3067.
unpublished results.
]
)^J^,
60.
Hopkins, P, B.; Fuchs, P. L. 2- Or£. Chem.
61.
Roberts, D. D,; Hendrickson, W, 2- 9LZ.' Chem.
2415.
62.
Stone, T, E,; Daves, G. D. , Jr. 2* 9l^'
63.
Kharasch, M. S,; Brown, H. C, 2* Am. Chem, Soc. }^^y
3432,
64.
Hageman, H. J.; Havinga, E.
88, 97,
65.
Dickens, D.; Frey, H. M. ; Metcalfe, J.
li^^y
34,
^^J^y
Chem.
Rec. Trav. Chim.
42, 1208,
A?.* 2151.
61,
Pays-Bas
1969,
''"^
Trans. Faraday Soc.
-im- ^ ' 2328.
66.
Georing, H, L.; Abell, P. I,; Aycock, B. F. 2* Am. Chem. Soc.
67.
Nelson, K. L.; Blackham, A. U. "Correlated Organic Laboratory
Experiences"; Brigham Young University Press: Provo, Utah,
1975; pp 25-26,
68.
Kohler, E. P.; Tishler, M.; Potter, H.; Thompson, H. T.
2- Am. Chem. 22£- } ^ ^ * ^^
1Q51.
69.
Braude, E, A.; Coles, J, A, 2- Chem. Soc,
70.
Braude, E, A.; Forbes, W, F.; Evans, E, A, 2- Chem, Soc,
1^50, 2014.
U ^ ' 2202.
71.
Nozaki, H,; Nisikawa, Y.; Kawanisi, M.; Noyori, R.
mL^
Tetrahedron
22, 2173.
Bull. Chem, Soc. Jpn.
}^J^y
72.
Hine, J.; Arata, K,
A2» 3085.
73.
Wohl, R. A.
74.
Moffett, R. B. In "Organic Simtheses"; Arnold, R. T., Ed.,
Wiley: New York, 1952; Vol. 32, p 41.
75.
Alder, K.; Flock, F. H. Chem. Ber. J^^,
76
House, H. 0.; Czuba, L. J.; Gall, M.; Olmstead, H. D. 2- Or^.
Chem. } ^ , 34, 2324.
77.
Riobe, 0.
78.
Croft, A. P.; Bartsch, R. A. 2- Org^. Chem.
Synthesis } ^ , 38,
89, 1732.
Bull. Soc. Chim. Fr. (Series 5) ^ ^ , 18, 829.
^ ^ , 48, 876.
Tetrahedron Lett, ^^^y
79.
Croft, A. P.; Bartsch, R. A.
80.
Seyferth, D.; Mai, V. A,
81.
Buckles, R, E.; Long, J, L, 2- Am, Chem. 2oc. ^^y
82.
Hageman, H. J,; Havinga, E. Rec. Trav. Chim, Pays-Bas 1966,
22, 1145,
—
-^
'^''^^^
83.
Olah, G. A,; Nojima, M,; Kerekes, I.
Synthesis, ^^^y
84.
Olah, G. A.; Nojima, M. ; Kerekes, I.
Synthesis, ^\^7^, 780.
85.
Cristol, S. J.; Bly, R. K. 2- ^m. Chem. 2££-
86.
Jarvis, B. B.; Govoni, J, P,; Zell, P. J.
J, Am, Chem, 2oc,
24, 2737...
I j ^ , 2i» ^412,
21, 998,
^^^y
779,
§ly 6155.
J, Am. Chem. Soc,
m i ' 11' 913,
87.
Luche, J, -L, ; Damiano, J. -C. J. Am. Chem. 22£-
88.
Rancher, S.; Klein, P, 2- 913.- Chem,
89.
Biehl, E, R,; Hsu, K. C, ; Nick, E. 2- Or^. Chem, ^J;^, 21»
90.
Bunnett, J, F,
91.
Ashby, E. C.; Goel, A, B,; DePriest, R, N, 2- ^ '
m i ' 102, 7779.
92.
Bartsch, R. A.
93.
Croft, A. P.; Bartsch, R. A,
94.
"Standard Proton NMR Spectra Collection"; Satler Research
Laboratories, 1973; Vol. 24, spectrum 15679.
95.
Snyder, H, R. ; Brooks, L. A. "Organic S5nitheses"; Wiley:
New York, 1943; Collect. Vol. II, p 171.
96.
Ross, S, D.; Finkelstein, M.; Peterson, R. C. 2- ^ '
Soc. , ^ ^ , 90, 6406.
97.
LeBel, N. A. In "Advances in Alicyclic Chemistry"; Hart, H.,
Karabatos, G. J., Eds.; Academic Press: New York, 1971;
pp 280-282.
98.
Hine, J. "Physical Organic Chemistry"; McGraw-Hill:
1962; p 487.
^^y
i^»
102,
46, 3558,
Ace. Chem. Res, }^X^y 2i» ^13-
Ace. Chem. Res. }^J^y
Chem. Soc.
2» ^39.
Tetrahedron
}^^y
22, 1417.
Chem.
New York,
APPENDIX:
CALCULATIONS METHODS FOR COMPETITIVE COMPLEX BASE REACTIOf
The two methods of data treatment for the competitive reaction
of two substrates with complex base (Equation 23) are described in
this Appendix.
One or the other of these methods was employed in
the calculation of values for the leaving group, 6-activating group,
and a-activating group effects, and the k ^./k
ratios. Equa° ^
^
*
anti syn
tions 23 and 24, where the two substrates (S.. and S») yield two
B
^1
+
^2
^
Pi
+
P2
(23:
(24:
V
products (P, and P^) by three base (B) promoted reaction routes
(k . k^, and k), show the general relationship of substrates to
products for these competitive reactions.
Initially, a method of calculation is described in which the
desired mechanistic parameters are derived from changes in substrate
concentrations
(Substrate Method).
Subsequently, a calculation
method is reported which utilizes product concentration data to
produce the required mechanistic parameters (Product Method).
Substrate Method
For the reaction given in Equations 23 and 24, a kinetic equatii
128
can be derived which involves only substrate (S^ and S2) concentrations and the kinetic rate constants for the reactions as variables.
The derivation of this equation is as follows:
Equations for the disappearance and appearance of all substrates
base, and products as a function of time can be written:
(25)
= k^[B][S^] + k[B][S2J
d[Pj
(26)
-d[S^]
dT—= (\^\nms^]
(27)
-d[Sj
^=k[B][S2]
(28)
-d[B]
-J—= (k + k,)[B][Sj + k[B][S-]
dt
a
b
1
2
(29)
Combining Equations 27 and 28 gives
-d[S^]
(k^ + k^)[B][S^]
(30)
k[B][S2]
-d[S2]
which, when placed into an equivalent form gives
dln[Sj
k + k,
1 _ _a
b
dliTIsp' "
(31)
k
Integration of this differential equation (Equation 31) between the
limits [S^]^ to [S^] and [S^]^ to [S^]
[S^]
[S^]
r
1
k
dlnTS^] = _a
rs 1
+ k,
b
dln[S2]
[sj
2o
(32)
gives
k + k
- ^
=
L
(33)
which defines the rate constants for the reactions solely in terms
of the substrate concentrations at a given time following the start
of the reaction ([S ] and [S.J) and the substrate concentrations
at the time of first analysis following the start of the reaction
([SJ
1 o
and [S_] ) .
Z o
The way in which the value for L (Equation 33) is applied to
the calculation of the desired mechanistic parameter depends upon
the specific experiment.
For the competitive reaction of trans-1-
chloro-2-fluorocycloalkanes and trans-1,2-dichlorocycloalkanes to
determine the leaving group effect, the parameters of Equations
23 and 24 are defined as
S-
=
trans-l-chloro-2-fluorocycloalkane
(34)
S-
=
trans-1,2-dichlorocycloalkane
(35)
P
=
1-chlorocycloalkene
(36)
k
= 0
a
The leaving group effect, in terms of L is given as
-HCl (6 to Cl) ^ _X- =
-HF (6 to Cl)
2k^
(37)
J^
2L
(38)
where a factor of 2 is included as a statistical correction for the
two possible syn dehydrochlorination pathways (of interest) from
the dichloride compared to the single syn dehydrofluorination
pathway of (of interest) available in the fluorochloride.
For the
1
competitive reaction of c i s - and trans-1,2-dichlorocycloalkanes to
determine ka n^t i. / k syn . the parameters of Equations
23 and 24 are
^
defined as
S^
=
trans-1,2-dichlorocycloalkane
^2
^ £i£-l,2-dichlorocycloalkane
(39)
(40)
P-, =
1-chlorocycloalkene
(41)
k
a
0
(42)
k
\
(43)
anti
=
atio k
k
syn
(44)
. ./ksyn is def
anti
anti
k
syn
k
\
1
(45)
L
For the determination of the a-activating group effect by the competitive reaction of trans-1,2-dichlorocyclohexane and (E)-l,2dichloro-1-methylcyclohexane, the parameters of Equations 23 and 24
are defined as
S.
=
trans-1,2-dichlorocyclohexane
(46)
S^
=
(E)-l,2-dichloro-l-methylcyclohexane
(47)
P
=
l-chloro-2-methylcyclohexene
(48)
P
=
1-chlorocyclohexene
(49)
k^ = 0
(50)
b
The a-activating group effect, defined in terms of L is given as
-HCl(6 to Cl, a to H)
-HCl(6 to Cl. a to Me)
_
a
2k
= - ^
2
(51)
where a factor of 2 is included as a statistical correction for the
two possible syn dehydrochlorination pathways (of interest) in the
]
trans-dichloride compared to the single syn dehydrochlorination
pathway (of interest) in the methyl dichloride.
Product Method
For the general reaction scheme given in Equations 23 and 24,
the desired mechanistic parameters can be calculated from the quan-
titative product concentration data for the two products (P- and P-)
In order to compensate for slight initial concentration differences
of the two substrates (S^ and S^) which may be present in a given
reaction and/or any anomolous reaction behavior, which may be presen
just at the onset of the heterogeneous reaction, the concentrations
for the two products have been defined as
[p^]
=
[Pjit
-
[P2I0
("
where [P2]^ and [P-^J^. refer to the concentrations of P^ and P at
some time after the start of the reaction and [P-] and [P ]
2 o
1o
refer to the concentrations of P and P at the time of first
analysis after the start of the reaction.
Three quantities A, B, and C can be defined as follows:
A
=
the concentration of P2 which was derived from S.,
(54]
B
=
the concentration of P^ which was derived from S
(55]
C
=
the concentration of P^ which was derived from S
(56]
In terms of P . P
A
=
[P,]
C =
[PJ
and B; A and C are
(57)
- B
(58)
Since an independent reaction of S. alone is possible, the ratio X
is known, where
X
=
-f
(59)
Thus, combining Equations 57 and 59 into Equation 58 gives
C
=
[P^]
- X[?^]
(60)
and combining equations 59 and 57 gives
B
X[V^]
=
(61]
Therefore, A, B, and C are defined in terms of [P,], [P^], and the
constant X, all of which can be determined by experiment (Equations
57, 60, and 61).
A statistical correction factor Z has also been defined, where
z o
The way in which the values for A, B, and C (which are calculate
from the product concentration data by Equations 57, 60, and 61) are
applied to the calculations of the specific mechanistic parameters
depends upon the specific experiment.
For the competitive reaction
of trans-1,2-dibromocycloalkanes and trans-l-bromo-2-chlorocycloalkan
to determine the leaving group and 6-activating group effects, the
parameters of Equations 23 and 24 are defined as
S., =
trans-1-bromo-2-chlorocycloalkane
(63]
S
=
trans-1,2-dibromocycloalkane
(64]
p
=
1-bromocycloalkene
(65]
p
=
1-chlorocycloalkene
(66]
The leaving group and 6-activating group effects, in terms of A, B,
C, and the statistical factor Z are given as
-HBr(6 to Br) _ 2C
-HC1(6 to Br) " B
-HBr(6 to Br) _
/^7N
^ ^
ZC
-HBr(6 to Cl) " T
,,«v
^ ^
For the competitive reaction of trans-1,2-dichlorocycloalkanes and
trans-l-bromo-2-chlorocycloalkanes to determine the leaving group
and 6-activating group effects, the parameters of Equations 23 and
24 are defined as
S-
=
trans-l-bromo-2-chlorocycloalkane
(69)
S^
=
trans-1,2-dichlorocycloalkane
(70)
P^
=
1-chlorocycloalkene
(71)
P-
=
1-bromocycloalkene
(72)
The leaving group and 6-activating group effects, in terms of
A, B, C, and the statistical factor Z are given as
-HBr (6
-HCl(6
-HCl(6
-HCl(6
to
to
to
to
Cl) ^ B_
Cl)
ZC
Br) ^ _A_
Cl)
ZC
^ -^
.
^'^^