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 . . . . 39

IV

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-ethanoanthra-cene 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 43

trans-[(2-Chlorocyclohexyl)oxy]trimethylsilane . . . 43

trans-2,3-Dichlorotetrahydropyran 44

(E)-l,2-Dichloro-l-methylcyclohexane 44

Preparation of Authentic Samples of Elimination Products. 45

1-Bromocycloalkenes 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 54

VI

Standard Complex Base Elimination Procedure . . . . 54

Competitive Complex Base Elimination Procedure . . . 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 57

Compound Purity Determinations 58

Analysis of Elimination Reaction Mixtures 58

Molar Response Studies 59

III. 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 81 Competitive Syn and Anti Dehydrochlorination

Induced by Complex Base 87

Leaving Group and B-Activating Group Effects . . . . 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-chloro-cyclohexane Induced by NaNH2-NaOCR- R R- in THF at Room Temperature 73

4. Elimination Reactions of trans-l-Bromo-2-chloro-cyclohexane Induced by NaNH2-NaAnion in THF at Room Temperature 79

5. Syn Eliminations from trans-l-Bromo-2-chlorocyclo-alkanes Promoted by Base 83

6. 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

7. 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

8. Leaving Group Effects for Eliminations from trans-1,2-Dihalocycloalkanes Promoted by NaNH2-NaO-_t-Bu in THF at 20.0°C 101

9. B-Activating Group Effects for Eliminations from trans-1,2-Dihalocycloalkanes Promoted by NaNH2-Na0-_t-Bu in THF at 20.0°C 102

10. 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

11. Dehydrohalogenations from Elimination Substrates Containing Non-halogen B-Activating Groups, In­duced by NaNH2-Na0-_t-Bu in THF 114

12. 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 cis-or trans-1,2-Dichlorocyclododecane 94

6. Schematic Representation for the Possible Elimination Pathways for Competitive Reaction of Two trans-1,2-Dihalocycloalkanes with Complex Base 99

CHAPTER I

INTRODUCTION

Elimination reactions are among the most widely studied reac­

tion 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 elimina­

tions. 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 mole­

cule 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 possi­

bilities 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

1 2 2

many years ' and has been the basis of much study. A presently

accepted mechanism (Equation 1) accounts for the often observed

second-order kinetics (first order in base and first order in sub­

strate) 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

+ -C" I

»

•C-

I X

B

H

I —C C' I

^ BH 4^C3ZC"+ X (1)

3 leaving group X, Hanhart and Ingold 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 intro­

ductory section.

In addition to the simultaneous loss of H and X in an elimina­

tion 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: , H ^ 1 . 1 . K

- c — c - Z ^ -c c — > H" + C ~ C _ - X (2) I < I

X ^-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. The mechanism involves two steps

(Equation 2): 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), This mechanism involves the loss of the

" ^1 k

2 + -C C- < BH + -C C- > BH +^CIZ:C^ X (3)

' X -1 I I k »

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 approxi­

mation 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 and

Rappoport. 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 addi­

tion 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 reac­

tions. 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 appro­

priately be described as a transformation within a single mechanism

rather than a change between two coexiting mechanisms. As envisioned

by Jencks, 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 actu­

ally 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. The reader is referred to an excellent

2 monograph on the subject. 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 elimi­

nation 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 rup­

ture 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 I I H

•C: r

I • c -I I

X

ElcB-like

1

B I I I

H I I I I

C-I I I

X

Central

2

B

H I I

-Cr-rrr:C-I :

X

El-like

3

Figure 1. 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

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 con­

trols the degree of double bond formation. Thus, central E2 transi­

tion states can have a high degree of double bond formation (product­

like transition state), or very little double bond character (reac-

tant-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-

12 lar 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

1 o

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

8

B I I

+ H-C—C+ + X I I

BH + C—C + X

u p u D. 3 U X I

t /

El-like /

/

/

Product­like Central

/

/ Central

/

/ /

h

Reactant-like

Central

/

ElcB-like

/

I I C-H rupture B + H-C—C-X

I I

_ I I BH + C—C-X

I I

Figure 2. More O'Ferrall Potential Energy Surface for Elimination Reactions

to rupture of the C-H bond would be represented by a pathway follow­

ing the left-hand, then top borders of the diagram; while a syn­

cronous 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

12 conjunction with these plots: (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 stabi­

lized 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 rela­

tive effects of variations in the reaction upon the reaction mecha­

nism. 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

13 in simple processes by use of the Hammond Postulate 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 elimina­

tion 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

16 as the Hammett equation (Equation 4).

log r- = pa (4) ^o

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. 2

Sigma (o) values have been defined for a number of substituents.

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 elimina-

2 tion reaction systems.

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. For example, the introduction of

,B ,a

H—C C—X

I I ^B ^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 elimina-12

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). Such data can be

very useful in mechanistic elucidation. Typically, the order of

leaving group reactivity is I>Br>Cl>>F for base-promoted dehydro­

halogenations. 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 sub-

20 strate. Similarly dramatic rate and orientation effects have

been observed in many cases by a change in solvent for a given base,

21 such as t_-BuOK from DMSO to t -BuOH.

Attempts to correlate rate data with base strength for a par­

ticular set of reactions was suggested more than 60 years ago

22 by Br^nsted. Application of the Br«insted rate law (Equation 5)

to a general base catalysed reaction allows a proportionality con­

stant e to be determined when k (reaction rate constant), K^ (ioni­

zation 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 coeffi­

cients 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 transi­

tion 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

23 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.

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-peri-

planar (6) corresponds to a dihedral angle of 0° conformations

5 and 6 are often referred to as those for trans and cis elimina­

tion in the chemical literature. However, the use of the cj^ 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 reac­

tion. Two other conformational variations are also recognized.

16

H

Anti-periplanar Syn-periplanar

6

X

Anti-clinal

7

Syn-clinal

8

Figure 3. 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

26 The classic work of Cristol with the benzene hexachloride

(1,2,3,4,5,6-hexachlorocyclohexane) isomers demonstrated the general

17

preference for anti elimination stereochemistry which has been

26 termed the Anti Rule. In his study, Cristol 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

CI

H CI

CI H

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

2 shown to exhibit preferential syn elimination. 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

27 reaction with 1^ (anti elimination).

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 28

ion. Zavada, Svoboda, and Pankova, in their detailed analysis

of t^-BuOK-induced elimination from 5-decyl tosylate, have demonstra­

ted that the degree of base association influences the stereochemi­

cal course of the reaction (Table 1). When an effective K com-

plexing agent (dicyclohexano-18-crown-6) was present for the reac­

tions 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 -/

/

/ H

\ \

\ s

B - — —

_ C ^ \

\ \

\ X

/ /

/ /

- M

12

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

n-Bu-CH tl-' jL-BuOK

-n-Bu > n-BuCH=CH-n-Bu

cis and trans

conditions

^6"6

C H 'fxlE 6 6

_t-BuOH

^t-BuOH+CE^

DMF

%

anti—> trans

33.6

63.9

24.8

67.1

73.2

%

syn—> trans

12.4

4.1

4.2

4.7

2.8

%

anti—> cis

50.4

29.2

68.2

26.7

22.6

%

syn—> cis

3.6

2.8

2.8

1.5

1.4

CE = dicyclohexano-18-crown-6

20

relative to anti by associated bases. Examination of transition

state 22 shows that the preference for syn elimination may be

explained on geometrical grounds. While the syn elimination pro­

vides 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 butane

(Equation 6) can give rise to three products in theory. The three

CH. CH^ CH H

CH^CHCH^CH. > C=C + ;C=C + CH2=CHCH2CH3 C6)

E E H CH^

products illustrate the two types of orientation which are encoun­

tered 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 pro­

ducts produced by a common mechanism from the same substrate, pro­

duct proportion differences are attributed to differences in trans-

sition 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 orien­

tation 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

31 (the thermodynamically more stable product). 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. Detailed discus-

2 sions of these effects are available elsewhere.

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 gen­

erated sodium alkoxide (or sodium enolate) in ethereal solvents,

such as tetrahydrofuran, have been shown to promote novel elimina-

32 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 trans-

34 1.2-dihalocycloalkanes. Caubere and Coudert 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-bromocyclo-

hexene (syn elimination of HBr) and 36% of cyclohexene (debromi-

nation 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

Br H

H Br

NaNH -NaO-_t-Bu

THF, Room Temp.

60%

(7)

36%

1-halocycloalkene products are not produced. The 3-halocycloalkene

and 1,3-cycloalkadiene products predominate.

The remarkable ability of complex base to facilitate preferen­

tial syn elimination has been the subject of only limited mechanis­

tic study. A cyclic six membered transition state interaction 13

32 33 36 has been proposed ' * 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 tran-

29 sition state due to geometrical considerations.

Importance of the alkoxide component identity in the complex

base upon the outcome of the reaction of trans-1,2-dibromocyclo-

37 hexane has also been assessed. 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

' u H Br

H

Br H

Anti

Eliminatio Isomerisation

H

(8)

3-bromocyclohexene with complex base gave no detectable 1-bromo­

cyclohexene. 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-dihalocyclo-

alkanes which contained two different halogen atoms. Thus, treat-

39,40 ment ' 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 pro­

ducts) , 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 dehydrochlorina­

tion 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 elimina­

tion 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-chloro­

cyclohexene.

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 sub­

strate 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-dihalo-

cycloalkane 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 deter­

mination of leaving group and B-activating group effects. An

analogous determination is envisioned for competitive dehydrofluori-

nation 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 competi­

tive reactions of a series of cis- and trans-1,2-dichlorocyclo-

alkanes 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 elimina­

tion 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 conduc­

tivity 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). Six chroma­

tographic columns were employed in the research: 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 Chromo­

sorb 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 Chroma­

tograph B. Detailed information on the gas chromatographic analyses

employed in this study is contained in a latter section of this chap­

ter.

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. The dibromide gave a satisfactory elemental

analysis. 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 128-

130°/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

40 A previously prepared 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 mole­

cular chlorine in the dark, in analogy with a procedure reported

for the preparation of the cyclohexyl analog, gave 6 g of a

crude material. 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

38 A sample which had been prepared by Lee 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 gave an essentially quanti­

tative yield of cis-cyclododecene. 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

46 the spectrum previously recorded.

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 condi­

tions) 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

42 Weinstock, Lewis and Bordwell.

33

Cyclobutyl amine was prepared via a modified Curtis rearrange­

ment from cyclobutanecarboxylic acid. Thus, 28,4 g of the acid

47 was treated according to the reported procedure 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 48

previously. 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

42 ion exchange resin according to a published procedure and in

analogy to a previous report. 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 quater­

nary 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

40 trans-l-Bromo-2-chlorocyclohexane (vide infra). Preparative GLPC

(Column D operated at 125°C) afforded 1.03 g of the pure trans-1-

bromo-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: C, 28.35; H, 3.57. Found: C, 28.54; H, 3.61. 4 o

trans-l-Bromo-2-chlorocyclopentane

40 A previously prepared 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 reac­

tion 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. Distillation (bp 73-74°/4.5 torr

40 (Lit. 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). The purest fraction boiled at 116-118°/

18 torr. Anal. Calcd for C^H^2^^^1= ^' 39.74; H, 5.72. Found C,

39.94; H, 5.69.

trans-l-Bromo-2-chlorocyclooctane

38 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).

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 previ-

40 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

40 The method of Lee was followed. 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 dis-

40 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-fluorocyclo-

heptane, 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 ClF: C, 55.81; H, 8.03.

Found: 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: C, 53.64; H, 8.34. 6 11

trans-l-Bromo-2-methoxycyclohexane

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

38 Material prepared previously 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: The method of Wittig and Mayer

was employed. 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-

52 2-fluorocyclohexanol proceeded according to a published report.

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,

52 Lit. 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 triphenyl-

phosphine in 100 ml of carbon tetrachloride, following the procedure

53 of Isaacs and Kirkpatrick. 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. Reaction

was found to be complete after 3 days. The compound boiled at

70°/l.l torr, 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. The reaction was stopped

after two days. 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

45 method) was accomplished using the method of Nozaki and Noyori.

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: The title compound was prepared

from cis-epoxycyclododecane 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 speci­

fied 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-9,10-ethanoanthracenes

trans-ll,12-Dichloro-9,10-dihydro-9 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-dihydro-9,10-ethanoanthracene

Treatment of anthracene with cis-1,2-dichloroethylene (Columbia

Organics) at 200°C for 24 hours in a sealed tube according to the

27 method of Cristol and Hause 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

27 to the published procedure ) gave the desired compound, contaminated

(10%) with anthracene. 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 phenyl-

sulfenyl chloride (0.060 mole) in 60 ml of methylene chloride

60 according to the procedure (1/lOth scale) of Hopkins and Fuchs

afforded the title sulfide. 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-cyclohexen-

1-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 satu-

rated, employing the procedure of Roberts and Hendrickson. The

product chlorohydrin (bp 88-89°/10 torr. Lit. 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 hexamethyldisila-

zane 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-dihydro-

211-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 solu­

tion 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

62 with that previously published. 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-methyl-

63 cyclohexene according to the procedure of Kharasch and Brown,

64 as previously employed by Hageman and Havinga. 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. Prepara­

tive 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,2-

dichloro-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, trans-

l-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. A micro boiling point

determination gave material with bp 185-186°/amb (Lit.^^ bp 66.5-

67.5°/13 torr).

1-Bromocyclooctene

38 A previously prepared 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-chloro-

cyclobutene and 1-bromocyclobutene , which was shown to be pure

(>997) by GLPC (Column C operated at 60°C) and identified by comparison

65 of GLPC retention times.

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 phos­

phorus 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-chlorocyclo-

heptane 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

38 another worker, 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-dichloro-

cyclododecane with 0.5 M _t-BuOK-_t-BuOH at 50°C for 48 hours (standard

t-Bu0K-_t-Bu0H elimination procedure, vide infra) . Employing the same

58 71 stereoselective dehalogenation procedure ' 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)-l-

chlorocyclododecene.

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

72 procedure of Hine and Arata 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. In each case, the corresponding dimethyl

ketal was the contaminant. The fraction determined by GLPC to be

95% pure 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

40 the previously published spectrum.

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

74 1,3-Cyclopentadiene (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 purifi­

cation for the next step of the reaction. Employing the published

method, 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. bp

108°/amb.

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 distilla­

tion, 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 evapora­

tion 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 isomeriza­

tion 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). Evaporation of the solvent gave 0.25 g of a yellow oil.

The 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

60 sulfide was in agreement with the published spectrum.

1-Cyclohexen-l-yl Phenyl Sulfone

The slow addition of 2.4 g of DBU to trans-2-chloro-l-cyclo-

hexyl 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 gave 2.7 g of the

title compound. Capillary GLPC (Column E) showed the compound to

be 97''< pure. The ^H NMR spectrum of the product sulfone is in agree-

60 ment with the published spectrum.

53

Miscellaneous Elimination Products

ll-Chloro-9,lO-dihydro-9,10-ethenoanthracene

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 distilla­

tion 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) round-

bottomed 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 ultra­

sonic 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-

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

55

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 pro­

ducts (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 facili­

tate 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 elimina­

tion 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 Elimina­

tion Procedure (vide supra).

Control Experiments

The elimination reaction procedure just outlined was followed,

with the exception that an authentic sample of the elimination pro­

duct (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 tempera­

ture 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 tempera­

ture 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 cor­

rected 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. The molar response

40 correction factor has been defined 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 chroma­

tograph.

Table 2 lists (in alphabetical order) the internal standard, gas

chromatograph, and value of the molar response for each of the com­

pounds in this study for which data has been used in calculations

60

TABLE 2

Molar Response Values

Internal Gas Molar Compound Standard Chromatograph 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

1-chlorocyclohexene

1-chlorocyclooctene

o-xylene A 0.806

toluene A 0.699

o-xylene A 0.849

1-chlorocyclopentene £-xylene A 0.661

1-chlorocyclopentene £-xylene C 0.647

ll-chloro-9,10-dihydro-9,10- triphenyl- C 0.867 ethenoanthracene methane

5-chloro-3,4-dihydro-2H-pyran toluene C 0.508

61 TABLE 2 (Continued)

Compound Internal Gas Molar Standard Chromatograph Response

trans-l-chloro-2-fluorocvcloheptane £-xylene

trans-l-chloro-2-fluorocyclohexane tolune

trans-l-chloro-2-fluorocyclopentane £-xylene

trans-l-chloro-2-fluorocyclopentane £-xylene

tran9-l-chloro-2-methoxycyclohexane toluene

(1-cyclohexen-l-yloxy)trimethyl- toluene silane

1-cyclohexen-l-yl phenyl sulfide toluene

2-cyclohexen-l-yl phenyl sulfide toluene

1-cyclohexen-l-yl phenyl sulfone toluene

trans-1,2-dibromocycloheptane £-xylene

trans-1,2-dibromocyclohexane toluene

trans-1,2-dibromocyclooctane £-xylene

trans-1,2-dibromocyclopentane £-xylene

trans-1,2-dichlorocyclododecane £-xylene

cis-1,2-dichlorocycloheptane £-xylene

trans-1,2-dichlorocycloheptane £-xylene

cis-1,2-dichlorocyclohexane toluene

trans-1,2-dichlorocyclohexane toluene

cis-1,2-dichlorocyclooctane £-xylene

trans-1,2-dichlorocyclooctane £-xylene

cis-1,2-dichlorocyclopentane £-xylene

trans-1,2-dichlorocyclopentane £-xylene

A

A

A

C

c

c

A

A

C

A

A

A

A

C

A

A

A

A

A

A

A

A

0 . 7 0 1

0 . 8 5 1

0 .546

0 .556

0 .870

0.792

1.20

1.00

1.30

0 .774

0 .740

0 .729

0 .845

1.00

0 .952

0 .857

0 .893

0 .826

0 .697

0 . 7 9 1

0 .730

0 .700

62

TABLE 2 CContinued)

Compound Internal Gas Molar Standard Chromatograph Response

trans-1,2-dichlorocyclopentane

cis-11,12-dichloro-9,10-dihydro-9,10-ethanoanthracene

trans-11,12-dichloro-9,10-dihydro-9,10-ethanoanthracene

o-xylene

triphenyl-me thane

triphenyl-me thane

C

C

C

0.619

0.850

0.843

(E) -1,2-dichloro-l-methylcyclo-hexane

toluene 1.37

trans-1-fluoro-2-methoxycyclo-hexane

1-methoxycycloheptene

3-methoxycycloheptene

1-methoxycyclohexene

3-methoxycyclohexene

1-methoxycyclopentene

3-methoxycyclopentene

toluene

toluene

toluene

toluene

toluene

o-xylene

o-xylene

C

C

C

C

C

C

C

0.907

0.913

0.926

0.792

0.800

0.580

0.607

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 mixed halogens)

to the corresponding alkenes. 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

81 8' (to give in situ bromine chloride ' ) produced the trans-1-bromo-

2-chlorocycloalkanes. Preparation of the trans-l-chloro-2-fluoro-

64

65

cycloalkanes was accomplished by treatment of the cycloalkenes with

O O Q A

N-chlorosuccinimide and Olah's * hydrogen fluoride-pyridine

reagent. However, repeated attempts to prepare the cyclooctyl

analog by this method proved futile.

The necessary cis-1,2-dichlorocvcloalkanes were generally pre­

pared from the corresponding cycloalkene oxides by treatment with

triphenylphosphine and carbon tetrachloride according to an exten-

54 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, cis-

and 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

60 sulfone.

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-chloro-

3,4-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-methylcyclo-

hexene.

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 isomeriza­

tion 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 > ( CI H

D Br

1 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.

39 40 Additional work by Lee and Bartsch * 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 NaNH2-

Na0-_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-fluoro-

cyclohexane 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.

37 Preliminary work by Caubere and others 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

37 found that more ramified R groups enhanced the proportion of dehydro-

39 40 bromination. In light of the discovery by Lee and Bartsch ' 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-2-

chlorocycloalkane 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.

tions

Previous work in the area of complex base-promoted elimina-

32,33,39,40 . , ^ ,. , has also shown the preference for 3-halogen-acti-

vated syn elimination relative to unactivated anti elimination from

trans-1.2-dihalocycloalkane substrates (Equation 10). However,

\/Unact ivated

Anti Elimination

X H

H

B-Halogen- H r-activated /

> ^

Syn Elimination H

H

(10)

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 inter­

actions 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.

39 40 Lee and Bartsch's observations ' 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 ) > ( ) (11)

H Y

group, 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 presen­

tation 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

37 Caubere and coworkers have demonstrated that variation of

R in the complex bases NaNH2-NaOR has an effect upon the relative

proportions of debromination and dehydrobromination from trans-

1,2-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-1,2-

dihalocycloalkanes, a study of the effect of alkoxide component

variation in the complex base upon the competing dehydrohalogenations

78 of a mixed dihalide substrate was undertaken. 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.

Br H

H CI

17

NaNH -NaAnion

• > + THF, Room Temp.

(12)

18 19

Results from the reactions of the substrate ] ^ with 27 combinations

1 2 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

1 2 3 by NaNH2-NaOCR R R in THF at Room Temperature

Time , J -, Required „-j,a

For NaNH2-NaOCR R R for ^°— Total 7 2 3 Consumption %18 + %19 Yield

System R R R"* of 17(h) (x 100) 18 + 19'

2

3

5

6

7

8

9

10

11

12

13

14

15

16

17

18

n-

n-

n-

n-

n-

•^5^11

- S ^ 5

•S»19

" ^ l A 3

"^17^35

s-Bu

2.-BU

t -Bu

Me

Et

n - P r

n.-Bu

il-^6^13

Et

n - P r

j . - P r

s-Bu

H

H

H

H

H

H

H

H

Me

Me

Me

Me

Me

Et

Et

Me

Me

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

b

Me H H 24 51 51

24 37 8

21 45 28

28 62 70

26 49 56

21 54 41

1 60 59

1 60 84

1 64 71

1 60 64

1 55 52

1 58 56

1 62 69

>1 62 28^

1 54 54

1 60 56

2 61 56

1 61 73

74

TABLE 3 (Continued)

12 2 Required a For NaNH2-Na0CR R R- for '^~

Time Requ: for '"^ Total

1 2 3 Consumption %1^ + %1^ Yield System R R R of 17(h) (x 100) 18 + 19'

19 i.-Bu Me H 1

20 t-Bu Me H 1

21 - ^ 4 ^ 8 - « 1

22 -^sHio- H 1

23 Me Me Me 2

24 Me Me Me 0.5

25 Et Me Me 1

26 Et Et Me 2

27 CF^ H H 1

28 CF^ CF^ H >24

59

65

62

54

65

3

65

63

59

64

36

83

59

68

87

76

83

80

79

33^

Standard deviation of ±1% in repetitive analysis of reaction

mixture. Standard deviation of ±2% from repetitive analysis

c of a reaction mixture. Reaction was incomplete. Product data

are after 1 h of reaction. 15-crown-5 was present in the reac-

tant ratio of j7 :NaNH2-NaO-_t-Bu:15-crown-5 = 2:3:6. Reaction

was incomplete. 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 dehydrochlorina­

tion 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 with the

leaving group. A comparison of systems 23 and 24 (Table 3) shows

that the introduction of an equimolar (with Na ) quantity of 15-

crown-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

39 after 24 hours 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 quanti-

37 tative yields of 2^ and _19. Caubere and coworkers 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-hexa-

fluoropropanol (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. The

reasons for these conflicting reactivities are not known. However,

both perfluorinated 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

87 88 mixture, and the recent successful rate enhancements reported *

for certain heterogeneous reaction systems when subjected to ultra­

sonic 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 com­

ponents 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

Anion of System NaNH2~NaAnion

29

30

31

32

33

34

35

36

phenoxide

£-methoxyphenoxide

£-methoxyphenoxide

benzoate

propanoate

enolate from 2-butanone

_t^-butylthiolate

thiocyanate

Time Required for Consumption of 17(h)

1

1

1

>4

>4

1

2

1

7,ia

%18 + %19 (x 100)

62

60

61

71

68

57

62

55

Total

Yield

18 + 19_m

80

69

81

4a,c

12^,c

53

89

57

Standard deviation of ±1% in repetitive analysis of reaction mixture,

Standard deviation of ±2% from repetitive analysis of reaction

mixture. ^Reaction was incomplete. Some starting material and much

cyclohexene were seen. 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

89 and NaCHPhCN in this study, was prompted by the report 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 rea-

90 91 gents ' ) , 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; respec­

tively) 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 compo­

nents 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 trans-

1J2-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 cyclo-

alkane substrate upon the competitive dehydrobromination and dehydro­

chlorination induced by complex base, a series of trans-l-bromo-2-

chlorocycloalkanes (20, n = 2-6) was subjected to complex base

(Equation 13). Variation of the value for n in 20 allows eliminations

(13)

H H

_20 li 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 (Experi­

mental 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 ^ and ^ , and the com­

bined yields of and _22 are given in Table 5. Parallel results

obtained from the reaction of the substrates with the more tradi-

r

83

m Ed

<

ca «

> ua •o 0)

o 6 O u tu CO 0) c (0

.^^ i H CO O

i H U >^ o o u o

i H u I

CM I

o E O 1^

pa I

i H I

CO

c

§ u

M-i

00 c o

• H . U CO (3

M

CO

U o O

m

o PQ

i|

o 3

PQ I .

CM rH TJ CO rH +

O - H r-» H >« CM

CO

e 4

CM

&« O

+ s CM h ^ 8 <

u o u

0) p . 6 0) H B O o Pi

(X4

3

o CO

I

CO

c o

•H C U u o c a •H «« e •u a o O 0) CO CM cd s c 0) •H O U^ pe: H u o

CM CM

CO rH +

O "H r H H >-• CM

CM CM L-N ^ « O

+ s CM

00 o

CO o o ON

m ir> vo

u (0

CO CO

rH m

CO CO

CO CO

m m

00

CO 73

m

00 00 00 CM ON

o o

m m

CM

m m vO

NO <"

m CO

G O

•H C )-l -M O O P .

•H 14.4 g •U 3 O (J 0) CO CM CO e C <U •H O (4-1

P i H O O

N •H ui

O 00 CM

pel O

CM

x: C M

i n vO 00

(U

• CO (U

c (U .!«: r H CO 0

r^ 0 > . U 0 U 0

r H

.c 0 1

f-\

•0 c CO 1 0 6 0 V4

JO 1

r H

4-1 0

1-i CO 4J 0 •M

G • H

<U

oalk

en

ycl

u 0

0

Xi 1 1

r H <4-l

0

G 0

• H •P U 0 a 0 V4

a, 0) >

•H •M CO

^ <u

pei 0

4J <U

r-i

a e 0 u G

M 0

• u (U 0 0 M CO

f-i

CO • H

V4 0) > 0)

.c u

•H 43 :»

«% a«« CM

U 0

<0 3

r-i CO >

•0 0) u CO •u CO

s th

e

0) 6

•H 4J

CO 0

• 0

CO • H

>% 4J

c • H CO U U 0) U G 3

73 (U •P CO

e •H •U CO

.ra

• u

C <u CO 0) M a. o| CNl

•a (U 4J 0 CO 0) >-i

c 3

<u B 0 CO

.c 4J • H >

C 0

• H 4J U CO

<u u 0) 4J 0)

r H

a 6 0 0

c M •0

sen

t.

<u M a o | CM]

T J

4J 0 CO

<u Vl G 3

.C u 3

a .c •M •H :»

G 0

• H 4J CJ CO

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_-BuOK-

benzene 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

29 92 and others ' 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 concentra­

tions 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-dihalocyclo-

alkanes 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 demon­

strated 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 dehydrochlorina­

tion 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 dehydro­

bromination (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

12 29 39 40 92 been proposed ' •» » ' for eliminations by both complex base

and t_-BuOK-t_-BuOH, such interactions (which would favor preferential

removal of the normally poorer, ' but more electronegative leaving

group) 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. Only in the

cyclooctyl case does dehydrobromination predominate. Perhaps this is

due to weakened base counterion-leaving group interactions which re­

sult from steric interactions between the complex base surface and

79 the cyclooctyl ring residue. 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 han do c o r r e s p o n d i n g r e a c t i o n s wi th t_-BuOK-£-BuOH.

. . 7 Q

This is consistent with the proposal that the complex base-promoted

eliminations have transition states with stronger base counterion-

leaving 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

1 0 QQ *30 / C\

complex base, has been established by previous work ' ' *

(Equation 10). Comparison of the relative rates of B-halogen acti­

vated 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.

2ft Cristol's classic study of elimination from the benzene

hexachloride isomers (1,2,3,4,5,6-hexachlorocyclohexane isomers)

has shown a strong preference for anti stereochemistry in dehydro­

chlorination (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\ H CI

V CI 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, competi­

tive 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

CI

23 anti

(CH2)^

^^»2)n

CI CI

H H

24

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)

(™2>n

H + CI CI

(CH2)„ NaNH2-Na0-_t-Bu

THF, 20.0°C ->

(CH2)^

(14)

23 24 25

90

allowed the calculation of k^^^./k for these reactions. The ant 1 syn

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

2 fi encountered (7000-24,000 for k ./k from Cristol's work

anti syn

discussed above). 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 Identity of trans-1,2- of cis-1,2- Ring Size Dichloride Dichloride of Z3 Substrate Substrate and~24

22 24 5

±2 24_ 6

2_3 24 7

22 24_ 8

26 27

k ^ . a a n t i

k syn

15 .0 ±

10.2 ±

8.8 ±

36 .5 ±

0 .13 ±

1.6^

0 .9

2 . 1

4 . 5

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.

27 by Cristol and Hause 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-dichloro­

cycloalkanes (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. There is then

an abrupt increase for the cyclooctyl system. 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

92

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 elimina­

tion 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 sub­

strate (22 or 22).

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

\

CI

(Z)

30

CI

H X

28; X = CI, Y = H

29; X = H, Y = CI

I

CI

CE)

31

Figure 5. Competitive Syn and Anti Dehydrochlorination from cis- or trans-1,2-Dichlorocyclododecane

CI

>

/ H

28; X = CI, Y = H

29; X = H, Y = CI

^ — ^ _ _ >

+ 1

CI

30

CI

31

(15)

analysis of the product 1-chlorocyclododecenes, and determination

of the appropriate product ratio led to values for k ^-/^ which

are recorded in Table 7. For the purpose of comparison, results

95

TABLE 7

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 50.0^0

Identity of Identity of anti Substrate Base/Solvent^ k

syn

28 A 25

29 A 18

28 B 38

a b A = NaNH -NaO-_t-Bu, B = t -BuOK-t_-BuOH. Estimated uncertainty

of ± %.

96

for the reaction of 2^ with 0.5 M t-BuOK-_t-BuOH (following the elimi­

nation 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 inter­

actions 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 base-

proton 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-2-

chlorocycloalkane 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) / \ -HCKB to Br) ^ ^ " < h ^ H > 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-acti-

vating 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 Y

32

-HX(6 to Y)

V

(CH2),,

-HY(6 to X)

(CH^)^.

X H

H X

33

-HX(6 to X)

i <™2>n

H' Y

34

X H

35

-HX(6 to X)

-HY(6 to X)

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-Dihalocyclo-alkanes 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 trans-

l-bromo-2-chlorocycloalkane and trans-1,2-dibromocycloalkane (Equa­

tion 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 +

H Y

32

(CH^) NaNH -^ " \ NaO-E-Bu

X H J > VTHF, 20.0°C

H X

33

(CH.) , 2 n (CH2)^,

(17)

34 35

C_-C^) of trans-l-chloro-2-fluorocycloalkane and trans-1,2-dichloro-

cycloalkane (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-dichloro-

cyclooctane, and complex base. The leaving group effects and 6-acti­

vating 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-1,2-

dihalocycloalkanes, promoted by complex base have been determined.

101

TABLE 8

Leaving Group Effects for Eliminations from trans-1,2-

Dihalocycloalkanes Promoted by NaNH -NaO-t -Bu

in THF at 20.0°C

Leaving Group Ring Size of trans-1,2-Dihalocycloalkanes Effect —

S 6 S S -HBr(6 to Br)^ -HCl(6 to Br)

-HBr(6 to Cl)^ -HCl(6 to CI)

-HCl(6 to Cl)^ -HF (6 to CI)

1.3 ± 0.4 1.1 ± 0.2 2.5 ± 0.2 2.7 ± 0.2

2.2 ± 0.7 1.9 ± 0.1 4.3 ± 0.9 5.9 ± 0.9

0.91 ± 0.2 0.40 ± 0.1 0.32 ± 0.04

Obtained from the competitive reaction with complex base of trans-

1,2-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-bromo-

2-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).

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

102

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 trans-

1,2-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-bromo-

2-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-dihalo-

norbornanes (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 Br to be a more efficient

B-activating group than CI. 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 6-Activating Group Effect

Value

-HBr(6 to Br) -HCKB to Br)

-HBr(p to CI) -HC1(6 to CI)

24

15

-HBr(6 t o -HBr(6 t o

-HCl(6 t o

Br) CI)

Br) -HC1(6 to CI)

3.5

2.2

105

(CHBr^>CHBr2Cl>CHBrCl2>CHCl3) reported by Hine.^^ Hine^^ found

that substituent halogens, a to the extracted proton, exhibit facili­

tation 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-chloro-

2-fluorocycloalkanes (C -C ) used in this study (no detectable 1-

fluorocycloalkene 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. The eliminations from 2 ^ have been

97 reported 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 dehydro­

bromination to dehydrochlorination is instructive. While the value

for the effect decreases upon going from dehydrobromination to dehydro­

bromination to dehydrochlorination for the norbornane systems, the

complex base systems exhibit an increase in the value of the 6-acti­

vating 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 character at C in the transition state. ' *

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 c — /' 6 / \ / \

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 interactions) can be attributed to a

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. The results of these two experiments are presented

below.

109

2,3-Dichlorotetrahydropyran provides two possible 6-chloro-

activated syn dehydrochlorination pathways (Equation 18). Elimina-

0 + ( 0 (18)

Cl Cl H

39 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 elimina­

tion substrate, 38^ was prepared and treated with NaNH2-NaO-t_-Bu in

THF at room temperature (employing the standard complex base elimina­

tion procedure found in the Experimental Section). After 6 hours,

no starting material remained. GLPC analysis gave a 15.1% yield

of 40, and no detectable 22* 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 substi­

tution 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-dichlorocyclo-

hexane was undertaken (Equation 19). While the kinetics of complex

NaNH2-Na0-2-Bu

THF, 20.0 C >

Cl

+ (19)

Me Cl

43 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). Subse­

quent 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-chloro-

activated 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, replace­

ment 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-dihalo-

cycloalkane substrates proceeds via a transition state with signifi­

cant carbanion character at C^, and little or no carbocation character p

at C , which is consistent with the results of the experiments dis-a

cussed earlier in this chapter.

Elimination from Substrates with Non-halogen 6-Activating Groups

32,33,39,40 , , , • . .u *. *• A Investigations undertaken prior to the present study

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-1,2-

dihalocycloalkanes (Equation 21; X=R=halogen).

(CH.). Un- H/-(C«2^\ '- . , f/^'"2^n 2 " \ activated / ""X Activated /

H ] < k X H > I ) (21) Anti H\ / Syn Elimination ^ ^ Elimination H 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-methoxy­

cyclohexene, 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 dehydro-

40 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 propor­

tions 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 proce­

dure given in the Experimental Section (Equation 22). The results

of these experiments are given in Table 11.

TABLE 11

Dehydrohalogenations from Elimination Substrates

Containing Non-halogen 6-Activating Groups,

Induced by NaNH2-NaO-2-Bu in THF

114

System Number

37

38

39

40

41

42

43

44

45

46

47

Substrate A5. X

Br

Br

Cl

Cl

F

Cl

Cl

Cl

Cl

Cl

Cl

R

OMe

OMe

OMe

OMe

OMe

OMe

OMe

OTs

OTMS

SPh

S02Ph

n

3

3

3

3

3

2

4

3

3

3

3

Reaction Tempi erature(°C)

r. t.

50°

r.t.

50°

50°

50°

50°

r. t.

r.t.

r.t.

r.t.

Reaction Time (hr)

24

5

144

5

120

1

1

24

1

2

0.25

%47^ %46 + %47 (x 100)

18

58

81

91

100

19

70^

0

0

94

100

%Yield 46 + 42^

90

91

33^

77

9

92

51^

0^

0^

93

93

^Estimated uncertainty of ±2%. 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. Cyclo­

hexene oxide was recovered as the major product.

115

H , (CH^ ,

X

H

H

-> H

(C«2>nX V^'^2)n

H + (22)

45 46 47

Three substrates of type 42 were also treated with 0.5 M ;t-BuOK-

2-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 elimina­

tion 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

48

49

50

Substrate X R

Br

Cl

Cl

OMe

OMe

OTMS

45 n

3

3

3

Reaction Time (hr)

24

24

24

%42^ %46 + %47 (x 100)

0

c

_d

%Yield 46 + 47

21"

0"=

0<

a b „

Estimated uncertainty of ±2%. Reaction was not complete - 78%

of the starting material remained. No elimination products were

detected. GLPC analysis showed 89% of the starting material

remained. 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 trans-

l-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 elimina­

tion 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 pro­

ceeded 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-1-

chloro-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 percen­

tages of syn and anti elimination can be assessed for trans-1-halo-

2-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. This is consistent with Bunnett's

41 Element Effect 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 elimina-

39 40 tions. ' For the syn elimination, induced by complex base, a

reversal of the normal leaving group ordering usually observed *

39 40 for base-promoted dehydrohalogenations has been observed. *

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-2-

methoxycycycloalkanes 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 sub­

strates 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-2-

methoxycyclohexane, 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.

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3. Hanhart, W.; Ingold, C. K. 2- Chem. Soc. }^^y 997.

4. Hughes, E. D. 2- Am. Chem. 2o£« /t^» AZ.» O^.

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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

^1 + ^2 B ^ Pi + P2 (23:

V

(24:

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) concen­

trations and the kinetic rate constants for the reactions as vari­

ables. 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:

= k^[B][S^] + k[B][S2J (25)

d[Pj (26)

-d[S^]

dT—= (\^\nms^] (27)

-d[Sj ^ = k [ B ] [ S 2 ] (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^]

-d[S2] k[B][S2] (30)

which, when placed into an equivalent form gives

dln[Sj k + k, 1 _ _a b

dliTIsp' " k (31)

Integration of this differential equation (Equation 31) between the

limits [S^]^ to [S^] and [S^]^ to [S^]

[S^]

r 1 k + k, dlnTS^] = _a b

[S^]

dln[S2] (32)

rs 1 [sj 2 o

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 and [S_] ). 1 o 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 (37) a

The leaving group effect, in terms of L is given as

-HCl (6 to Cl) ^ _X- = J^ -HF (6 to Cl) 2k^ 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 react ion of c i s - and trans-1,2-dichlorocycloalkanes to

determine k ^ . / k . the parameters of Equations 23 and 24 are a n t i syn ^

defined as

S^ = trans-1,2-dichlorocycloalkane (39)

^2 ^ £i£-l,2-dichlorocycloalkane (40)

P-, = 1-chlorocycloalkene (41)

(42)

(43)

(44)

k a

k

\ =

atio k

anti k syn

0

anti

k syn

. ./k is anti syn

k

\

def

1 L (45)

For the determination of the a-activating group effect by the com­

petitive reaction of trans-1,2-dichlorocyclohexane and (E)-l,2-

dichloro-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

= - ^ (51) -HCl(6 to Cl, a to H) _ a -HCl(6 to Cl. a to Me) 2k 2

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^] = [ P j i t - [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 1 o

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 and B; A and C are

A = [P,] (57)

C = [PJ - 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 /^7N

-HC1(6 to Br) " B ^ ^

-HBr(6 to Br) _ ZC ,,«v

-HBr(6 to Cl) " T ^ ^

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 to Cl) ^ B_ -HCl(6 to Cl) ZC ^ -^ -HCl(6 to Br) ^ _A_ . -HCl(6 to Cl) ZC ' ^