Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

116
MIGRATION TENDENCY OF SUBSTITUENTS IN SOME CATIONIC REARRANGEMENT REACTIONS by YEN-LONG VINCENT HONG, 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 Accepted May, 1982

Transcript of Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

Page 1: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

MIGRATION TENDENCY OF SUBSTITUENTS IN SOME

CATIONIC REARRANGEMENT REACTIONS

by

YEN-LONG VINCENT HONG, 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

Accepted

May, 1982

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••'V -'l 7 '

. • / • ,• ^ • '

n j ^ - u v '<-»---»

ACKNOWLEDGEMENTS

I am deeply indebted to Dr. John Marx for his guidance in this

dissertation, to Dr. Joe Adamcik for his helpful criticism, and to

other committee members and colleagues who have aided in the direc-

tion of this work. Appreciation is expressed to the Welch Foundation

for financial support for the experimental work.

11

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TABLE OF CONTENTS

ACKNOWLEDGEMENTS ii

LIST OF TABLES vi

LIST OF FIGURES vii

I. INTRODUCTION 1

The Rearrangement of the Electronegative Functional

Group 2

The Pinacol-Pinacolone Rearrangement 3

The Dienone-Phenol Rearrangement 5

The Aromatization of Cyclohexadienols 12

The Relative Migratory Aptitude and Migration Tendency. . 14

The Migration Tendency of Et and Me 17

Scope and Purpose of the Present Work 22

II. RESULTS 24

Preparations of the Compounds for These Kinetic Studies . 24

Rearrangements of 4-Methyl-4-R Cyclohexadienones {5)... 32

Rearrangements and Migration Tendencies of 4-Methoxy-4-R- ^

Cyclohexa-2,5-Dienones (R = Me, Et, COOEt) Ta, , 2^ • • ^^ Rearrangements of 4-Methyl-4-R-Cyclohexadienols (r=Me, Et,

and COOEt) 8a_, 8b, 8c_ 47

Reactions of 4-Methoxy Cyclohexadienols (9) 52

Rearrangements of Pinacols (lOa, lOb, and lOc) 53

Suramary 63

III. DISCUSSION 65

General 65

Electronic Factor in Each System 66

iii

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M!' CH3

Change in Rate-Determining Step for Rearrangement of

Pinacols 2P in CF^COOH/CH COOH 68

Transition States for Dienone and Dienol Rearrangement. . 72

Tool of Increasing Electron Demand 73

Value as a Probe 75

Temperature and Solvent Effects 77

Carbethoxy as a Migration Group 77

IV. CONCLUSION 79

V. EXPERIMENTAL 81

General 81

P r e p a r a t i o n s of 4 ,4-Dimethylcyclohexa-2,5-Dienone (5a) and 4- í fe thyl -4-Ethylcyclohexa-2 ,5-Dienone (_5b) 82

P r e p a r a t i o n of 4-Methyl-4-Carbethoxycyclohexa-2,5-Dienone (5c) 83

Preparation of 4-Methyl-4-Methoxycyclohexa-2,5-Dienone (_7a) 83

Preparation of 4-Ethyl-4-Methoxycyclohexa-2,5-Dienone (_7b) 84

Preparation of 4-Methyl-4-Carbethoxycyclohexa-2,5-Dienone (7c) 84

Preparation of 4,4-Dimethylcyclohexadienol (8a) and 4-Methyl-4-Ethylcyclohexadienol (8b) 86

Preparation of 4-Methyl-4-Carbethoxycyclohex-2,5-Dienol iSc) 87

Preparations of 4-Methyl-4-Methoxy- and 4-Ethyl-4-Methoxy-cyclohex-2,5-Dienols (9a and _9b) 88

Preparation of 4-Methoxy-4-Carbethoxycyclohex-2,5-

Dienol (^) 89

Rearrangement of 4,4-Dimethylcyclohexa-2,5-Dienone (5a) . 89

Rearrangement of 4-Methyl-4-Ethylcyclohexa-2,5-Dienone (5b) 90

IV

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Rearrangement of 4-Methyl-4-Carbethoxycyclohexa-2,5-Dienone (5c) 90

Protonations of Dienone (_5a) , (_5b) , and (^) in CF^COOH . . 92

Rearrangement of 4-Methoxy-4-Methylcyclohexa-2,5-Dienone (7a) 92

Protonation of Methoxy Dienones (_7a, Th^, and 7^) in 1:1

Ratio of CF-,COOH/CH COOH 93

Rearrangement of 4,4-Dimethylcyclohexadienol (8a) 94

Rearrangement of 4-Methyl-4-Ethylcyclohexadienol (8b) . . . 95

Rearrangement of 4-Methyl-4-Carbethoxycyclohexadienol (8c) . 95

Reactions of 4-Methoxy-4-R-Cyclohexadienols (9) 96

Rearrangement of l,l-Diphenyl-2-Methyl-l,2-Propanediol (lOa) 96

Rearrangement of l,l-Diphenyl-2-Methyl-l,2-Butanediol (IQb) 97

Rearrangement of l,l-Diphenyl-2-Carbethoxy-l,2-Propanediol

(lOc) 98

Rearrangement of Epoxides 34a, 34b, and 34c 99

LIST OF REFERENCES 100

APPENDIX lO'

V

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LIST OF TABLES

I. Preliminary Approximate Relative Rate of Compounds _5, 7 , and 10 bv NMR Spectroscopy 21

II. Rearrangement of 4-Methyl-4-R-Cyclohexadienones (_5) in

CF^COOH 33

III. Rearrangement of Dienones (_5) in TFAA/TFA (25°) 37

IV. Rearrangements of Dienones _5 in Aqueous H«SO, at 25 . . . . 39

V. Protonation of Compound 2]^ 4L

VI. Rearrangements of Dienones (T ) in CF^COOH/CH^COOH at 25 . . 44

VII. Rearrangements of Dienones "]_ in Aqueous H«SO, 45

VIII. Rearrangements of Dienols 8 in Acidic Solutions at 25 . . . 49

IX. Rearrangements of Pinacols ( W in CF^COOH/CH^COOH at 25° . 55

X. Product Ratio of 10 in CF^COOH/CH^COOH 56

XI. Rearrangements of Pinacols (10) in H SO.-HOAc-H^O at 25°. . 61

XII. Summary of Migration Tendencies 64

VI

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LIST OF FIGURES

1. Plot of log (A -A) vs. time for lOa in CF,,C00H/CH.3C00H at

25° °°. . 7" "T". . . ? . . . ? 54

2. NMR spectrum (60 MHz) of product mixture of lOb in CF.3COOH/-CH^COOH 57

3. NMR spectrum (100 MHz) of product mixture from rearrangement of lOb in CF^COOH/CH^COOH after the NMR shift reagent, Resolve Al EuFOD™, was added 58

4. NMR spectrum (100 Miz) of product mixture from rearrangement of lOb in H^SO^-HOAc-H^O after the NMR shift reagent, Resolve Al EUFODTM^ was added 62

5. p-a plot of 37 and 38 on 70% aqueous dioxane at 25 C. . . . 74

Vll

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CHAPTER I

INTRODUCTION

The intraraolecular 1,2-shift (Wagner-Meerwein rearrangeraent) of a

substituent to a cationic center was first discovered in the bicyclic

terpenes, and raost of the early development of this reaction was per-

formed with these compounds. For this reason it is often illustrated

with an example from the terpenes, e.g,,

R R^ R 1 ^ \ ''+ "-- ^ \ I

— C C+ > >.l lC ^ +C C —

Isoborneol camphene

However, it raay be illustrated in sirapler systeras:

CH„ 1

CHr C CH^ 3 1 2

CH3

CH^CH^CH^Br

Cl 0H~ H^O^A

AlBr

/

> 7

f3 CH3 C

Br 1 CH^ CH

— CH —

CH3

CH3

Relative migratory aptitudes for this type of rearrangements

usually follow the order aryl> H>alkyla The order is related to the

ability of a substituent to stabilize a positive charge in the transi-

tion state of the rearrangeraent, though many other factors are

usually of some importance in determining which group migrates in a

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particular system.

The Rearrangement of the Electronegative Functional Groups

In contrast, another type of migrating group undergoes analogous

migration with relative ease, yet is a type of group which should not

stabilize the cation readily. This type is the electronegative

functional group, in which the atom actually undergoing the migration

is itself relatively positive due to the normal polarization of the

entire functional group. The rearrangement of these electronegative

species, such as keto, ester, cyano, and nitro groups, have been

observed in three main type of systems.

Most of the exploratory and all of the early mechanistic work

has been done in the pinacol-pinacolone rearrangement of epoxy ketones

1—8 and esters under a variety of acidic conditions.

Ph \

H 0

-<:H

0 II c CH,

BF - H3C C-

II 0

Ph

C I H

•CHO ref. 2

R,

ref. 4

L) R = R^ = CH.,; b) R = H, R„ = Ph; c) R-, = R., = H

Examples of rearrangement with aromatization, all involving

carbethoxy migration, in dilute sulfuric acid have been reported. 9,10

The aromatization had been carried out in mono- and bicyclic dienones

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NO mechanistic study was reported.

COOEt CH

dilute H,,SO, 2 4

3 \ COOEt

0

COOEt

50% H^SO, 2 4

9 hr • ^

COOEt

The third type of rearrangement is the raigration of the electro-

negative species to siraple localized carbonium ion centers in open

chain compounds. Examples of carbethoxy migration and of phosphorus-

11 12 containing species * were studied.

0 T Ph

> - C

CH 0 ^H

P^OC^H^)^

- ^ T B F ^

0 t

Ph P(OC/,H.)/, \ X 2 5 2

CH, CHO

Among these studies, the pinacol and dienone-phenol rearrangement

are often used as examples. Therefore, let us first look at these

reactions in detail.

The Pinacol-Pinacolone Rearrangement

The pinacol rearrangement derives its name from Fittig's original

observation that sulfuric acid transforms tetramethyl ethylene glycol

(pinacol) into methyl jt -butyl ketone (pinacolone) , and this type of re-

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arrangement can be represented by the general scheme as below (Scheme

I), in which R , R^, R3, and R, represent hydrogen atoms, alkyl

groups, or aryl groups.

R,

R, R,

OH OH

R.

Scheme I

This reaction has been accomplished many times and is a well-

known process. In most cases each carbon has at least one alkyl or

aryl group, and the reaction is most often carried out with tri- and

tetrasubstituted glycols. Glycols in which the four R groups are not

identical can give rise to more than one product, depending on which

group migrates. Mixtures are often produced, and which group migrates

preferentially may depend on the reaction conditions as well as on

the nature of the substrate. If at least one group is hydrogen, then

aldehydes can be produced as well as ketones.

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In addition to the pinacolic transformation proper there exists

a number of closely related rearrangements which belong to the

same class of chemical transformations. They are the rearrangements

of ethylene oxides, 2-amino alcohols, and halohydrins to carbonyl

compounds. All these reactions proceed through the same type of

13 carbonium ion intermediate as does the pinacol rearrangement.

The mechanism of the pinacol rearrangement is usually written

as follows:

R-, R/, R, R/, R, R/, ^ ' ^ ^ -H.O l l

R, =-^ Ro - C - C - R, R , > — C — C — R / > R^ — C 2 I I 4 -= 2

OH OH OH OH^ ÔH 4 ^ "2

ir -

+

+ R, R

2

1

^ R„ C — C — R , s, R o — C C R 4 ^ 2 II , 4 OH R/, 0 R3

It may seem odd that a migration takes place when the positive

charge is already at tertiary position, but carbonium ions stabilized

by an oxygen atom are even more stable than tertiary alkyl cations.

There is also the driving force supplied by the fact that the new

carbonium ion can be immediately stabilized by losing a proton from

oxygen to give a carbonyl group.

The Dienone-Phenol Rearrangement

A substituted dienone may undergo rearrangement and aromatiza-

tion of the dienone ring in acid solutions. The course of the re-

arrangement is through one or more 1,2-shifts in a benzenonium ion

intermediate, and the products are usually phenols or aryl acetates

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depending on the acidic media.

A common practice is to treat the dienone in acetic anhydride

solution with a small amount of concentrated sulfuric acid at room

temperature. The product is an aryl acetate. This is usually

separated and hydrolyzed to the phenol either with base or by boiling

with aqueous acid. Another common practice is to treat the dienone

with either aqueous sulfuric or hydrochloric acid. In that case the

product is the phenol.

2 ^ "'

-H + • ^

-H + — ^

OAc

R.

R,

Scheme II

The earliest known example of the dienon-phenol rearrangement,

the rearrangement of santonin to deismotroposantonin acetate, is

14 from the natural products field. One of the simplest examples

is the rearrangement of 2,4,4-trimethylcyclohexadienone to pseudo-

documenol. The reaction of santonin involves a 1,2-shift of the

methyl group, but many similar rearrangements involve intermediate

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CH.

dilute H^SO, 2 4

- ^

Ac^O, H^SO^ -^

\ ^ CH. AcO

CH3 ^ O - ^

CH,

cations with spiran structures, and require more than one 1,2-shift

to accomplish the transformation. This was first inferred from a study

of the rearrangement of the dienone _1, which gave the acetate 2^ rather

than 3.

OAc

AcO

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The proposed mechanism is shown in Scheme III:

8

AcO

1,2 shift

AcO

OAc

Scheme III

The first detailed study of the migration of electronegative

substituents were carried out by Marx and co-workers in the

aromatization of the series of 4,4-disubstituted cyclohexadienone,

4 and _5, in which R=methyl (Me) , ethyl (Et) , isopropyl (i-Pr),

benzyl (Bz), and phenyl (Ph). The rearrangements were carried out in

trifluoroacetic acid to avoid possible ester hydrolysis.

COOEt

0 4

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18 Consideration of the dienone-phenol rearrangement mechanism

(Scheme IV) shows that there are three possible rearrangement path-

ways depending on the substituent R.

R COOEt

i -1

R COOEt.

' + '

OH

A

B

-^ C

COOEt

R

COOEt

Scheme IV

The first step is rapid and reversible, and the protonated

ion A is detectable by NMR spectroscopy. The rearrangement step is

rate-determining and irreversible, and is followed by rapid proton

loss which generates the aromatic ring. In the ion B (and thus the

transition state preceding it) the group R remaining behind can

stabilize the positive charge. However, if R migrates to give ion

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10

C, the CO«Et will become conjugated with the charge and act as a

destabilizing influence. Thus, ion B is of lower energy than ion

C and path a is followed when R=Me or Et.

However, if R=i-Pr, the isopropyl group is expected to be

better at migrating than methyl or ethyl, but poorer in stabilizing

ion B (and the transition state leading to it). Thus, one might

predict that isopropyl would migrate instead of carbethoxy and path

b would be followed. The benzyl group should stabilize ion B about

the same as methyl, and acts as a better migrating group than iso-

propyl. It was thus predicted that the benzyl group should migrate.

In fact, neither path is followed, but fragmentation via a carbonium

ion occurs instead. Evidently, ions of type C, with the electro-

negative substituent remaining behind are of too high energy to form

when other pathways are available.

Perhaps the most dramatic case was the one in which R=Ph. It

was found that CO, Et migration (Path a) occurred exclusively, in

spite of the fact that phenyl is usually a very good migrating

group. The compound rearranged 135 times as fast as the correspond-

ing methyl compound, reflecting the stabilizing influence of the

phenyl group if it remains behind instead of migrating.

An attempt was made to force the dienon-phenol rearrangement to

go through path b, by placing two carbethoxy groups in the migration

19 position. However, only fragmentation of an ester group occurred

in this case. This again gives supportive evidence that path b of

Scheme IV is a very high energy pathway and that reactions path c_ prefer

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11

COOEt COOEt COOEt COOEt COOE

^

0

COOEt

+ + 0 = COEt

It is now clear, from this study and others, that the group

remaining behind is the major factor that decides which group migrates

in cyclohexadienone compounds whenever an electronegative group is

placed in competition with an alkyl group. However the carbethoxy

group (andother electronegative groups) are polarized such that the

carbon atom undergoing the migration is positive and would therefore

appear to be a poor group to stabilize the positive charge in the

transition state of the migration. The postulate has been made that

7T bond of the carbonyl group has to back-donate some electron density

to the transition state for the migration reaction. In support of

this idea, the trichloromethyl group, for example which has similar

polarity to the carbethoxy group but lacks TT electrons, will not under-

21 22 go such migrations under any conditions. * The transition state

for carbethoxy group migration was proposed as shown below, with

migration being fairly advanced, so it resembles the product ion B

more than the starting ion A.

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12

The Aromatization of Cyclohexadienols

In addition to these two weil-known and much studied systems,

there exists another rearranging system that appears to have similar

characteristics, the aromatization of cyclohexadienols.

The dienol-benzene rearrangement is formally similar to the

dienone-phenol rearrangement but it provides several interesting

differences. The mechanism of this reaction is provided in Scheme V

R, R/

OH

R.

• ^

^-1

R R,

+ H^O

+ H

Scheme V

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13

A notable difference between this reaction and the dienone-

phenol rearrangement is the absence of a protonated carbonyl group

as the intermediate. This is thought to seriously affect the

kinetic acidity dependence of the dienone-phenol rearrangement be-

cause of the strong intermolecular hydrogen bonding to neighboring

water molecules. In the dienol-benzene rearrangement no such inter-

action is possible and therefore it may be a better system for

comparison purposes.

The dienol-benzene rearrangement of 4,4-dimethylcyclohexadienol

23 (8a) has been investigated. This compound shows convenient re-

arrangement rates in acetate buffers. Moreover, when a_ is dissolved

in dilute acid there is observed the formation of a new species

(A = 259 nm, £ 1600), which is identified as 8a' as in Scheme VI. max

CH, CH.

H+ +

(D) H OH

8a

CH '«3

H OH

+ H

H(D)

8a'

^

+ H +

H(D)

Scheme VI

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14

The intermediate (8a') forms £-xylene 20 times slower than it

is formed through isomerization from . The rates of isomeriza-

tion and rearrangement of in various dilute buffer solutions,

23 were reported and the rearrangement is hydrogen ion catalyzed in

acetate and formate buffers.

Monitoring Sa^ at A.259 nm shows evidence of a biphasic reaction,

i.e., the absorbance increases (due to the formation of the con-

jugated isomer) followed by a decrease in optical density due to the

formation of -xylene. Since the isomerization reaction was 20 times

faster than the rearrangement, these data were treated as separable

consecutive first-order reactions and very little error was introduced

by treating the data in this fashion.

Because the similarities and differences of this reaction with the

dienone-phenol rearrangeraent, it would be interesting to compare the

kinetic results between them.

The Relative Migratory Aptitude and Migration Tendency

In the early years, many people tried to establish a relationship

between the migration rates of compounds as a function of the migrating

substituent. The studies were always conducted by allowing two or

more substituents to compete for migration within the same molecule and

determining which group migrated by product studies. Such intra-

molecular comparisons give values which are termed "relative migratory

aptitudes". The general method for determining them is to generate

a carbonium ion at a position adjacent to two or three substituents

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15

which potentially can migrate and to observe the ratio of products

formed after the migration. The relative order of migration for

some simple substituents is usually Ph>Et>Me, which is the order of

ability of the substituent to stabilize cations. However, this

intramolecular comparison is often complicated by several factors,

such as the conformational preference of different substituents,

amount of charge density generated before rearrangement occurs, and

relative stability of the substituents to migrate. Thus, the

"relative migratory aptitudes" do not measure any property of the

substituent, and vary widely as the system is changed.

In order to cancel out raost of these complications, Stiles and

24 Mayer have studied the rearrangements of a series of glycols in

which the R group was varied. The migration of R was studied by

CH/, R

I 3 I CH/, "• C C CHo

3 I I 3 OH OH

a. R = CH3; b. R = C^H^; c. R = ^-C^H

intermolecular comparisons of the rates, using compound ^ (R = CH/j)

as the standard. Corrections were made, using labeling studies to

identify the various products. After the appropriate corrections,

t h e o r d e r of r e a r r a n g e m e n t of ^ in 50% H SO, was found t o be _t-Bu>Et>Me

with relative rates of >4000:17:1.0. Stiles and Mayer termed this

intermolecular comparison "migration tendency" M^„ , which is defined

un.,,

as Ki/Ki 3, where kp = partial rate constant under the defined

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16

conditions for migration of the group R. However, the validity of

the vaiue for the _t-butyl case as a measure of migrating ability has

^25 been questioned.

This migration tendency can also be appiied to the cyclohexa-

dienone system. As a matter of fact, it appears that the cyclohexa-

dienone system is superior to pinacol or any other known system for

studying such intermolecular comparisons, because most of the complicat-

ing factors mentioned earlier should be minimized or eliminated.

Thus both substituents are held in identical steric environments, so

no raigratory pref erence based on stereochemistry can occur. The reac-

tion is induced by protonation on the carbonyl oxygen, so no complica-

tion associated with leaving groups can occur.

Marx et_. al_. " have studied the rearrangements of compounds _5

where R = Me, CO^Et, and Ph, by NMR s pectroscopy. The migration

tendencies, in trifluoroacetic acid at 38.5 , fell into the order

Me<COOEt<Et<Ph, with relative rates of 1:14:55:260. The vaiue of ethyl

vs. methyl (55) in CF- COOH is almost identical to the value of 49 + 2

26 determined from the same two compounds in aqueous H-SO, and thus

appears to reflect a property of the system. This system actually

generates a carbonium ion which is stable enough to be observed by

NMR before it rearranges, and represents an extreme case in which

charge density is high before the migration occurs. Based upon an

21c NMR deshielding argument, a calculation that 0.15 of a positive

charge unit is at the migration terminus in the protonated cyclo-

hexadienone ion. In contrast, in any system in which there is a

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17

CH. R

0

5

H - >

R = Me, CO^Et, E t , and Ph

leaving group involved, the amount of p o s i t i v e charge bui ld-up i s

unknown and not de te rminab le , s ince the migra t ion can be more or

l e s s concerted with depa r tu re of the leaving group.

The Migrat ion Tendency of Et and Me

The migra t ion tendency of Et v s . Me in the dienone system i s

much g r e a t e r than in any o the r known system. For the p inacol r e -

24 arrangement of j6, i t i s 17, as mentioned above. For rearrangement

28 to a hydroxy- subs t i t u t ed c a t i o n i c cen te r in b is-_t -a lkyl ke tones ,

i t i s 2 to 5.

h R/c-C •C-

II 0

/1 C — R^

H + slow

R/,-C C -I OH

R'

-^

f a s t

R

\ \

R,

R,

OH R-

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18

For migration to a primary cationic center, in neopentyl type

29 30 compounds, * it is 0.5 to 1.0.

R' CH^OH R' ^CH^OH CH^OH

h + ^2 C CH^X ^ R^ C CH^R^

In these examples, the conformational effects were designed to

be minimized or eliminated, and the electronic effect is rather

important. Therefore, this dramatic trend appears to reflect, at

least qualitatively, differences in charge density which must be

stabilized by the migrating group in the transition state of the re-

arrangement step. In the neopentyl-type cases shown above, only a

little charge density may build up during the transition state of

the fairly concerted rearrangement. However, the dienone system

actually involves a carbonium ion species which is stable enough to

observe spectrally before it rearranges, so it represents a fairly

extreme case in which charge density builds up before the migration

step. Therefore the amount of charge density the migrating substituent

is called up to stabilize in the transition state is a much more

important consideration in determining which group migrates and how

fast.

If one considers the transition state for the raigration of a

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19

methyl v£. an ethyl group,

H H R

\ /

c .c

one notices that the group R attached to the migrating carbon atom

(R = H for a methyl group, and R = CH3 for an ethyl group) is in a

position to help stabilize the positive charge density. Thus, the

more positive charge density that is required to be stabilized in the

transition state, the better an ethyl group should be in migrating

as compared to a methyl group. If there is very little positive

charge density on the migrating group in the transition state, then

a methyl and an ethyl group should show little difference in how

fast they migrate. This idea seems to fit the known experimental facts,

and does not seem to have been pointed out in the literature. It

also seems to fit the concept perhaps best articulated by H. C.

31 Brown, which he calls the "tool of increasing electron demand".

Taking the argument one step further, it appeared that it might

be possible to use the migration tendency of the ethyl group (i.e.

its rate of migration as compared to methyl in the same system under

the same conditions) as a probe for the electronic requirements in

the transition state for the rearrangement in other systems. It

was hoped that one might even be able to use this information in a

predictive sense, at least qualitatively, to determine the migration

tendency of other migrating groups, especially the electronegative

ones (such as esters, ketones, nitriles, nitro groups, etc) in

Page 27: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

20

each rearranging system. The work described in this disertation

represents the first step toward examining this postulate.

The present work was initiated by a number of undergraduate

students in Dr. Marx's research group. These students, over a

period of several years, developed synthetic methods to produce all

the compounds in three rearranging series. These were the methyl

substituted dienones _5, the methoxy substituted dienones 1_ and the

pinacol series l^. Credit for the contributions made by these

students will be given when appropriate in the ensuing discussion.

Thus, it appeared to be of great importance to see how the

migration tendency for the groups Me, Et, Ph and COOEt would vary in

other systems for which a great deal of charge density had built

up before the rearrangement step occurred. It was desired to choose

systems in which conformational and other complicating features

would be minimized. Toward this end, three series of compounds were

s^mthesized and preliminary rearrangement data were determined. These

were the series 5, 7, and 10 in which R = Me, Et, Ph, COOEt.

CH R

0

CH3O R

0

7

Ph

Ph I C -

R I C

OH OH

10

•CH/

a, R = Me; b, R = Et; c, R = COOEt; d, R = Ph

Page 28: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

21

It was demonstrated that in almost all cases for these three

series, the group R migrates cleanly. For compound T, R = Ph,

a competing methoxy fragmentation reaction occurs instead. For

compound 5^, R = Et, ethyl migration is the major pathway (98%), but

2% of methyl migration also occurs, allowing one to compute a

partial rate constant.

Preliminary approximate rate data had been obtained for these

rearrangements in trifluoroacetic acid. The results are dramatic

and unexpected, and are summarized in Table I.

Table I. Preliminary Approximate Relative Rate of Compounds , _7, and 10 by NMR Spectroscopy^.

Series

2

]_

10_

R = Me

1

1

1

R e l a t i v e Rate

R = Et R = Ph

55 26

300

6 25

R = COOEt

14

10,000

0 .001

The rate data group were obtained by raeasuring the decrease of the raethyl group signal in each starting compound in CFoCOOH by NMR spectroscopy, and are based on estimating the half life, not on determining the rate constants. Each value was corrected, if necessary, for rearrangement of the goup R according to the product(s) study.

From the data in Table I, three trends were noted:

(i) The divergence of relative rates of OOOEt group is surprisingly

wide. Compared with methyl the variation is approximately a factor of

10 . It is extremely fast in the methoxy substituted dienone 2^, and

Page 29: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

22

extremely slow in the pinacol IQc.

(ii) The differences between methyl and ethyl migration rates

vary less widely. It is small in the pinacols (lOa and lOb) and shows

the largest difference observed to date for the methoxy dienone

(7a and _7_b).

(iii) When the difference between methyi and ethyl is small,

COOEt acts as a very poor migrating group; and when the difference

is large, COOEt is a very good migrating group.

Scope and Purpose of the Present Work

These trends suggest that electronic factors, especially the

amount of charge density the substituent is called upon to stabilize

in the transition state is the major factor which determines the

relative rate at which the groups migrate. Furthermore, the results

are in at least qualitative agreement with the observations made

by others in comparing migration tendencies of raethyl and ethyl in

28,29,30 . .. . j . 1 other systems, as indicated previously.

Because all the measurements in Table I were obtained by the NMR

method and were carried out only in a preliminary way by undergraduate

workers, a more accurate UV method to determine the absolute migra-

tion rate quantitatively is necessary for compounds _5, ]_, and 10.

In addition to this, it was desired to determine the migration

tendencies of the three groups Me, Et, and COOEt in other rearranging

systems, i.e., 8 and 9_ and to look at solvent and temperature effects

briefly.

Page 30: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

CH„ ^ R CH3O. ^R

OH

8

OH

9

a, R = Me; b , R = E t ; c , R = COOEt.

-/~

z '

/

Page 31: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

CHAPTER II

RESULTS

Preparations of the Compounds for These Kinetic Studies

None of the compounds needed for this study are commercially

available, and thus had to be synthesized. Many of the compounds were

prepared previously by the undergraduate students in this laboratory.

Samples left by the previous workers were impure or not available in

sufficient quantity, and in some cases, the synthetic conditions

developed previously were not ideal. Therefore much time was re-

quired to prepared the compounds.

Even though all the corapounds have fairly simple structures,

some of the preparations are very challenging and tedious. Only two

of them (7a and 7b) are synthesized by one-step reactions frora

commercially-available starting materials. In this section, the

details of their preparation will be given individually. Credit

will be given to previous workers where appropriate.

The preparations of 4,4-dimethyl- and 4-methyl-4-ethyl-cyclohexa-

17 32 2,5-dienones (_5a and 5b) have been reported previously ' and are

summarized in Scheme VII.

The first step to make the enamine followed the method of

33 Benzing, and the subsequent cyclization gave a better yield (73%)

34 than the literature value. The dehydrogenation with dichlorodicyano-

quinone (DDQ) or SeO both gave the desired dienones (5a and 5b) .

35 The SeO^ method gives diselenide by-products. These diselenides

can be removed from the dienones by recrystallizing from CCl^, but

24

Page 32: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

25

RCHÍCH^^CHO + 'N H

A • R-C^CH^) = CH-N

R

(1) methyl vinyl ketone (2) piperidine acetate

CH/ R

SeO/

CH/

or DDQ

R = CH3, ^

= C^H^, 5b

Scheme VII

other selenium-containing impurities cause purification problems.

The DDQ method was thus the method of choice.

The preparation of _5£ was developed in these labs and is modi-

3 fi fied from the synthesis of related compounds by Pleininger. The

total synthesis of this compound is outlined in Scheme VIII.

CH CH COOEt HCOOEt

^ CH.,—C—COOEt NA 3 II

CH

Piperidine acetate

CHOH

COOEt

0

SeO,

CH/

methyl vinyl ketone KO-t-Bu

COOEt

CHO

CH/

or DDQ

Scheme VIII

COOEt

0 5c

0

4-Methyl-4-methoxy- and 4-ethyl-4-methoxycyclohexa-2,5-dienones

37 (7a and 7b) were synthesized by the method of McKillop, although

synthetic details for these specific compounds are not given by this

author. Thus, ^.-cresol or £-ethylphenol and thallium (III) nitrate

Page 33: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

26

were dissolved in cooled (0°C), dry methanol solution and stirred for

3 hr, followed by passing through the column of basic alumina and

recrystallization from either methanol or petroleum ether to yield

7a or Tb^. This reaction is easy to perform, although extensive

rechromatography was necessary to remove yellow impurities in both

cases. The yield in each case of the final highly purified crystals

was low (less than 25%) . In the case of the ethyl compound, a yellow

by-product was isolated, which was assigned the structure _11, based

on spectral evidence and mechanistic reasoning.

OCH/ R R OCH/

TKNO^)^

- ^

0

R = CH3, 7a

= C^H^, Tb

CH2CH3

11

In principle, the procedure for synthesizing 4-methoxy-4-carbe-

thoxycyclohexa-2,5-dienone (]c) is similar to the route used for c-

38 In practice, much developmental work was required to make this

previously unknown compound, due to the intermediacy of the highly

water-soluble compound U^. In fact, all attempts to isolate this

compound failed, but it could be trapped in aqueous solution when

the total product from the previous step was dissolved in water and

adjusted to pH8 and stirred overnight with excess methyi vinyl ketone

Page 34: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

27

(MVK). Some of product j^, resulting from reverse Claisen reaction

on 23. was also formed, but cyclization of the mixture Ad distilla-

tion gave the cyclohexenone J^ in reasonable yield. The oxidation

step proceeded much better with DDQ than SeO^. The procedure for

this totai synthesis is outlined in Scheme IX.

CICH COOEt NaOCH CH CH OH

> CH OCH COOMe — ^ - ~ > H

CH OCH COOEt

^ ^ ^ ^ CH,-C-COOEt N a 3 II

CHOH

12

methyl vinyl ketone pH8

CH3O C00Et^^3° ^COOEt

^ CHO H

+

13 0 0 14

CH 0

Piperidine acetate

0 15

COOEt

Scheme IX

CH3O

DDQ

COOEt

• >

0 7c

The preparation of 4,4-dimethyl- and 4-raethyl-4-ethyl-cyclohexa-

dienols (8a and 8b) are one-step reductions from _5£ and _5b with excess

23 LiAlH, in dry ether. Both reductions are quantitative (98%) and

no further purification is necessary. As a matter of fact, the

23 literature shows that attempted purification of results in

extensive decomposition to o -xylene. Both and are actually

about 1:1 mixtures of stereoisomers. Further separations of these

isomers are not necessary for our purpose, thus no attempt was made.

Page 35: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

28

CH R

0

excess LiAlH,

R = CH3, _5a

= C^H^, 5b

R = CH3, aa

= C^H^, _8b

It proved necessary to prepare 4-methyl-4-carbethoxycyclohexa-

dienol (8c) by a different method from that used for 8a. and 8b due

to the presence of the ester functional group. A survey of the

hydride reducing agents indicated that there are only a few reagents

which can reduce a carbonyl-group without reducing the double bond

and/or the ester fûnctionai group. Moreover, since dienols are

known to undergo aromatization readily, it was assumed that 8c_

might decompose during the purification process and therefore the

reduction would have to be absolutely clean. Many potential hydride

reducing agents were investigated and all failed to give cleanly.

For example, sodium borohydride and sodium borohydride on silica gel

both gave a mixture which contained decomposition product (£-cresol)

and some unidentified by-products. Sodium borohydride and cerium

39 chloride hexahydrate (in ethanol) reduction gave no reaction at

alla Lithium hydridotri _t-butoxy aluminate (in dry ether) reduction

gave the desired product (8c) but also produced up to 25% of the by-

product £-cresol.

Page 36: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

29

In the examination of the behavior of 9-borabicyclo [3,3,l]nonane

(9-BBN) as a reducing agent toward carbonyl functional groups, H. C.

40 Brown found that 9-BBN in tetrahydrofuran (THF) reduced aldehydes

and ketones rapidly and cleanly (to alcohols) even faster than it

hydroborated olefins without interfering with the ester and many

41 other functional groups. Danishefsky also reported, in the synthesis

of disodium prephenate, a very clean conversion from dienones to

dienols utilizing 9-BBN. More importantly, the dienols he prepared

have similar functional groups (ester, a,3- unsaturated) to show in

8c and purification by silica gel coluran chromatography was successful.

The dienone _5£ was found to be reduced cleanly by using 9-BBN/THF

(no detectable £-cresol according to NMR spectroscopy). Column

chromatography over silica gel gave pure (76%).

Dienols _9a, , and were synthesized by following the pro-

cedures already described for the dienols in series , using Ta , 7b,

and ]_c^ as the starting materials. The yields were lower compared to

dienols 8, presumably due to losses in the work-up procedure.

CH3O R

OH

9

R = CH3, ^

R = C^H^, ^

R = COOEt, 9c_

The syntheses of l,l-diphenyl-2-methyl-l,2-propanediol (lOa) and

l,l-diphenyl-2-methyl-l,2-butanediol (lOb) were accomplished by

Page 37: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

30

42 Rickey Gross and are outlined in Scheme X.

^^ r. r. Ph

^h—b—c( l > P h — C — cf ll ^«3 '''^ ^. "CH3

H_0, dioxane ?^ .0 ^^ 9^3

OH 3 OH OH

R = CH3, j ^

= C^H^, 2 ^

Scheme X

The bromination and hydrolysis steps followed the method of

43 Stevens, and both products were crystallized frora petroleum ether.

The Grignard reaction was investigated in ether, dioxane, and THFa

The THF medium turned out to be the best choice. After column

chromatography, lOa and lOb were recrystallized from petroleum ether

The large samples left by this former worker were pure enough for

the present work.

The preparation of l,l-diphenyl-2-methyl-2-carbethoxy-l,2-

ethyleneglycol (lOc) was tedious and difficult, and was also carried

44 out by Rickey Gross and other undergraduates. Scheme XI outlines

the synthesis of this compound.

The Reformatsky reaction of benzophenone and a-bromoethylpro-

pionate afforded l,l-diphenyl-2-carbethoxy-l-propanol (16). De-

hydration was unexpectedly difficult, but could be carried out with

Page 38: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

31

Ph \ (

y Ph

CH^CHBrCOOEt C = 0 -TT^—i >

Zn, Benzene

Ph Ph I I

Ph — C — C — COOEt I I OH H

16

SOCl,

Py -^

Ph

Ph

CH,

C = C \ COOEt

mcpba Ph \

/ ^ 3

Ph O COOEt

18

HCO Na - Ph —

Ph CH, 1 I -c — c -ocH m

IJ 0

19a

Ph

COOEt + Ph — C -I OH

19b

CH_ 1 3 C — COOEt I OCH JJ 0

NaOH -> Ph

Ph I C -

î«3 c — I

COOEt

OH OH

lOc

Scheme XI

S0C1_ in pyridine under carefully controlled conditions. The original

plan was to use cold alkaline KMnO, or peroxyformic acid to convert

17 to the final glycol product (lOc), but all attempts failed.

Therefore, the longer synthetic route shown above was followed.

Compound _17 was treated with m-chloroperbenzoic acid (mcpba) to yield

18 (93%). The alkaline H 0 epoxidation of Y]_ was also attempted

but mostly starting material (17) was recovered. Epoxide opening

under most conditions led, at least in part, to rearranged products

Page 39: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

32

via solvolysis. However, use of sodium formate gave rather clean

opening to a mixture of glycol monoformates. Selective hydrolysis

of the formate, leaving the ethyl ester intact, could be carried

out fairly well by treating the mixture of formates (19a and 19b)

with NaOH in THF/H_0 under carefully controlled conditions. The

yield of lOc calculated from opoxide J^ was 32%. Only a small amount

of the pure product was available from the previous workers, but it

proved to be sufficient for the current work.

Rearrangements of 4-Methyl-4-R Cyclohexadienones (5)

(A) In CF3COOH

The rearrangement products of _5a_, _5b, and _5£ in CF3COOH are 3,4-

dimethylphenol for _5a; 3-ethyl-4-methylphenol (a.. 98%) and 3-methyl-

4-ethylphenol ((ca_. 2%) for 2^; 3-carbethoxy-4-methylphenol for 5£,

according to the previous study. Kinetic results from the UV

study and data thus obtained from further treatment are suramarized

in Table II.

26 From the equation developed by Waring , the rate constant (k^)

of the rearrangement step depends on k , and the ratio of the

starting dienone and the protonated dienone ([B]y[BH ]),

k/, = k ^ (1 + [B^/^BH"^]) (Eq. 1)

2 obs ... 17

Trifluoroacetic acid does not protonate the cyclohexadienones fully ,

and the degree of protonation can be estimated by NMR spectroscopy.

Protonation causes a downfield shift of all signals in the NMR

Page 40: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

ix: o o o

cn o c

.H

(Ol

03 0) c o c Qi

•H T3 CO X 0)

o iH O >.

O I

peS I

< í I

iH >. U 0) S I

o

c (U B (U 00 d cd u u cd (U

PCÎ

0)

cfl H

c O

•H 4-1 cO U ÛO

a c (U

1 3 C (U

H

vO O r-l r-( 1

CJ X <u

æ a

O •

vO 03

CO r H vO

<X)

<r i H

vO O rH -H 1

U X (U

co CVI

O •

f^J i H

vO CM vO

<X) <r r H

vO

X I

o u o

o (U

M cn aO

o

c o

•H 4J CO >-( 00

•H S

co 4-1

c (U 3

4-1

X)

c

c o 6 o o

o >3-

csi 00

(U S

cn

O <y\.

ô ^ 0 0

a> •

cO O

• % » •

4-1

w

4J

w o O o

<u s (U

s

4->

w (U

s

w O O o (U

s

o CN

CtJ

in i n u m

00 (Ti CN

CO co <r

o m CM •<J-

CN i H O i H

co ^ 0 0

VO i H f O < ! •

CM r H O i H

CN

(JN ^ o vO

•<r CN

r>-. i H vO

(U

s

B 2 0 0 <y\

• cO O

>-/ 4-1

w

4-1

w o o o

(U

s (U

s

4-1

w (U

s

4-1

w o o o (U

s

o in

co aO i n

33

ca

Page 41: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

34

spectrum compared to the values in CCl,, and the shift is related to O T O "7

the amount of protonation. ' Complete protonation occurs in

H^SO^. For enones or acid-stable dienones such as 4-methyl-4-tri-

chloromethylcyclohexadienone, the vinyl protons a to the carbonyl

group are deshielded ca. 1.0 ppm and those 3 £a_. 1.3 ppm. The

dienones in Table II rearrange in H SO, too rapidly for accurate

observation of the protonated form. However, the enone precusors

(of , _5]b, and _5£) are only protonated in H SO, and show the ex-

pected shifts of the vinyl proton signals (a= 0.92+0.03, 3= 1.3+ 17

0.07). The downfield shifts of the vinyl protons of the dienones

(run as dilute as possible in order to approximate concentrations

used in the UV kinetic method) observed in CFoCOOH were measured by

NMR spectroscopy: ^ , a = 0.55, 3 = 0.72; Sh^, a = 0.52, 3 = 0.75;

5c, a = 0.36, 3 = 0.51. Assuming a linear relationship between the

downfield shift of the a- and 3-proton signals and the amount of pro-

tonation, the calculation gives ca.. 57% protonation for 5a^ and 5b,

39% protonation for at "infinite dilution". This has been taken

into account in calculating k..

The protonation behavior of dienones _5 can be calculated from

equation 2, in which ^•D*^-O-U-^» ^^^ ^ ^^^ ^^^ molar absorptivities of B BH

the unprotonated, protonated, and partially protonated dienones.

_ilL_ z. flSÍ ^ . • • • (Eq. 2) [BH+] ^ - B

If the same concentrations were used to measure these values,

equation 2 becomes equation 3, in which A^, A jj+» and A represent

Page 42: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

35

the absorbances of the unprotonated, protonated, and partially

protonated dienones.

[B] ^ ^H+ ' ^ [BH+] ^ - \ ' ' ' ^^'

Because trifluoroacetic acid does not protonate 5a^, 5b, or 5c

fully, a small amount of sulfuric acid was added to observe the A^ +

value. Full protonation occurs for 5a and 5b when 1.4% of H^SO, or

— — 2 4

more was added, and at least 1.8% H SO, is required for to be

fully protonated. The A^ values were.obtained in acetic acid solu-

tion, and A values were measured in trifluoroacetic acid. The cal-

culations gave 56 + 1% protonation for (the value for was

assumed to be the same as for 5a) , and 38 +^ 1% protonation for ^

in CF3COOH. These values are very similar to the ones obtained by

NMR spectroscopy.

The similar protonation behavior of and is parallel to

Waring's work, who found and also protonated to the same

extent in aqueous sulfuric acid solutions of various concentrations.

An interesting comparison was then made based on the acidity functions

of CF_COO H and aqueous H^SO, solutions. The NMR study concluded

that _5a and ^ both protonated £a_. 57% in pure CF3COOH, which has a / c O A

Hammett acidity function (H ) value of -3.30. Waring stated

that compounds 5a^ and followed the amide acidity function H^

within experimental uncertainty. However, no H^ values seem to be

available for CF3COOH. Since H^ varies linearly with the Hammett

acidity function over the acidity range studied, plots of log k

Page 43: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

36

against H^ are also linear. The H^ value of pure CF3COOH is similar

to the one for 49-50% aqueous H^SO^, which protonated 5a (and 5b)

26 £3.. 55%. This agreement further confirms the validity of the NMR

method used in the CF3COOH medium (which protonates _5a and Sb £a.

57%) within the experimental error.

The protonation of _5£ in CF3COOH (39%), measured by the NMR

method, is somewhat puzzling because the inductive substituent con-

stant (a^) of COOEt group (a^ = 0.35 in CF3COO H)^^ is greater than

the methyl and ethyl groups (a = 0.0), and a bigger difference in

protonation behavior is expected. However, since the NMR method is

proved to be valid, this value (39%) is then taken into account to

, , , COOEt calculate k

P

The partial rate constants, k , are then obtained by dividing

by a factor of 2 for _5a (a statistical factor to correct for the

fact that either of the two raethyl groups could migrate); and taking

product ratios into account for _5b . The raigration tendencies thus

obtained are M^^^.^^t .j COOEt ^ i.io3:24.7 at 25°; and 1:98:23.4 at CH3 CH3 CH3

45°.

These migration tendencies at 25 are somewhat different from

previous data (1:55:14) for the same dienones in the same solvent

and at the same temperature as measured by NMR spectroscopy. After

car'eful examination of the previous work, we found that the difference

could be attributed to the methods of preparing the solvent. The

trifluoroacetic acid was "purified" by distillating from P^O^ (as

drying agent) in the previous NMR study, which produced small amounts

of trifluoroacetic anhydride (TFAA) as well. The amount of anhydride

Page 44: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

37

generated depends on the quantity of P^O^ added and the refluxing

time. The influence of TFAA present in the solvent upon the reaction

was confirmed by obtaining different results (rate constant and

migration tendency) when solvents prepared by different methods were

used. Observing the reactions of compounds , Sb, and _5£ in the

mixed solvents of TFA/TFAA a general trend was found that the more

TFAA in the solvent, the faster the rearrangements proceeded for

every compound, and the relative migration rates became similar.

The data are presented in Table III.

Table III. Rearrangement^ of Dienones (5) in TFAA/TFA (25 )

^ \ C o m p o u n d

So lven t ^ - ^ . „ ^

10%^

20%^

40%^

Observed Rate Constant

22.7 63.4

9 7 O í. 1 .y

135 139

(x 10 ) sec

4 .85

11.4

31.2

Percentage of TFAA in TFA by volume

These data suggest a change in mechanisra is occurring. The

TFAA presumably forms the trifluoroacetyl-substituted carbonium ion

which then rearranges rapidly.

CH, R

(CF300)^0 I +

y

0-gCF 0 ^

-^

0-C-CF. 0-C-CF. 0

Page 45: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

38

This mechanism could compete with the normal protonation mechanism

to a varying extent, and is possibly dominant in 40% TFAA/TFA. Under

these conditions, and _5b rearrange at the same rate, suggesting

that the first step is rate determining. The inductive effect of

the COOEt group in _5£ would be expected to depress this rate, as is

observed.

(B) In Aqueous H„SO,

The rearrangement products for _5£ and ^ in aqueous H.SO, were

the same as in CF-COOH. However, for _5£, in addition to the rearrange-

ment product (3-carbethoxy-4-methylphenol, 20) , jg -cresol (which

results from hydrolysis of the carbethoxy group of the reactant,

see Scheme XII) was found as a by-product. As the concentration

of H/jSO, was decreased, larger percentages of .-cresol were found in

the reac tion mixture.

The overall rate constant (rearrangement and decarboxylation)

can be obtained by monitoring the decrease of UV absorption at 260

nm due to the disappearance of _5£. The percentages of the rearrange-

raent product (20) were estimated by NMR spectroscopy, and are £a.. 21%,

41%, and 68% in 52.0%, 60.8%, and 70.4% aqueous H^SO^ solutions,

respectively. The observed rate constants of the rearrangement were

then calculated based on these product ratios and are shown in Table

IV.

The kinetic results for the rearrangements of dienones _5 in

aqueous H^SO are given in Table IV.

Page 46: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

o i n CN

co

O

CNl

ffi Cfl

3 o <u 3 cr

< c

•H

m l

cn (U c o c (U

. H Q

CO 4-1 c <u B (U ûO c cú u u cd (U

OcS

<U

CO

H

c o •H 4J CO M ÛO

. H

s

>% o C (U

•a c <u H

vO O r- l t H 1

O X (U

cn o .

m ro

XI cr> r-l

^ /

o m cn

\o O rH

I

X o <U co

CN

vO

X I

o cu

co co x> o

c o

•H

a 3 O u o

cO

ûO

CO 4-1

c (U 3

CO XI 3

O

O

O <r o in m r m

CM O m o

CN

6^2 (30

(U

s cO

W

4J w o o o

13 c 3 O CU B o o

(U

s 4-i

w

4J w o o o

(U

s (U

s (U

s

o C M

m

co m

XI m m

cn

m r^

o f-^

r^ cn

o m co

o m r H

m CX3 r^ co

o m æ

a^ r^ O

X I o <r r>« m

CO m CN r H

>í co Cvj

P^ m 0 0 m

CO m CN r H

m co

o r^

•^ co

<u s

8 2 0 0 <Ti > - •

ca u w

4J

w o o o

C3 CN CN

r r <y\ m

CN o 0 0

(U

s

&>« 0 0 <y\ V w /

cO 4-1 W

4-J

w o o o

<U

s (U

s

4-1

w (U

s

4-1

w o o o

<u s

&>5 00

• O vO

cd m - l m

o m

<u s <u s

4-1

w (U

s

u w O O o (U

s

8^2

sr o

cú m m

o m

u o

4-1 o cd

<H

Cfl •H x: 4-1

u o

T3 (U 4J o (U U U O

o C (U (U

CO cd

JC

39

o co

CO

5>5 CM

CO u 3 o o O

C o

•H 4J ct3 $-1 ûû

•H

6 rC U 4J w a <U .JsJ

s

Page 47: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

40

CH/ COOEt

k.

CH/ COOEt

<-

"-1

0 0

H" , H^O

COOH CH COOH

-> y + I

OH

+ CO/

COOEt

20

Scheme XII

In order to sort out the rate constant for the rearrangeraent

step (k.), one has to know the protonation behavior of the compound.

28 Waring has reported a full set of k , and k values of 5a and

obs 2 —

_5b in aqueous H-SO,. Therefore this protonation behavior can be cal-

culated by incorporating his data for various concentrations of H_SO,

into equation 1. It was then calculated that _5a and both undergo

ca. 60% protonation in 52% H„SO, ; ca. 90% in 61% H,,SO, , and ca. 99% — f 2 4 — 2 4 —

Et in 70.4% H„SO,. The M^„ values we obtained (49) (see Table IV)

2 4 CH3 28

agree perfectly with Waring's value (49 + 1) in the same solvent

system.

The protonation behavior of _5£ in aqueous H^SO, is not measurable

because this compound tends to decarboxylate extensiveiy in strongly

Page 48: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

41

acidic medium. It was therefore necessary to try to estimate it.

47 Vitullo reported the protonation of 4-methyl-4-dichloromethyl

cyclohexa-2,5-dienone (21) (which does not rearrange) in aqueous

H^SO^ and Table V gives the [ BH"^]/[ B ] data:

CH, CHCl, CH

0

21

H +

CHCl,

\ I

0

21 +

Table V. Protonation of Compound 21

Wt. % H/,SO, 2 4

47 .38

52.47

55 .42

58 .95

62 .60

6 7 . 0 1

70 .44

72 .96

n ^ / 11

0.038

0.0680

0.105

0 .165

0 .326

0.734

1.80

3.07

-H o

3 .15

3 .65

3.95

4 .35

4 .78

5.35

5.87

6.25

According to Table V, compound ^ protonated £a.. 6% in 52% H^SO^,

£a. 20% in 60.8% H^SO^, and £a. 64% in 70.4% H^SO^. The inductive

substituent constant of CHCl is approximately the same as the one

Page 49: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

42

for the COOEt group. Because the protonation behavior in this type

of system in a given solvent depends on the a value of the sub-

stituent, it is not unreasonable to predict that _5£ would have some-

what similar protonation behavior to 21^, The M^^^^^ values were CHo

then calculated to be 10.0, 11,3, and 10.7 in 52.0%, 60.8%, and 70.4%

aqueous H^SO^ solutions using equation 1 and are listed in Table IV.

Note that these three numbers agree very well within experimental

error.

It appears to be reasonable that the difference in protonation

behavior between the ester compound and alkyl ones _5£ and 5b

would be greater in aqueous H SO, than in CF.,COOH, because the

46 46

hydrogen bonding and solvent polarity effects of the COOEt group

tend to increase the inductive effect of the polar group more in

aqueous H„SO, than in the CF.,COOH medium. Since most of these type

of measurements are made in the aqueous medium, perhaps it would be

more reasonable to say that the ester dienone _5£ shows anamolous pro-

tonation behavior in the CF/,COOH medium. Rearrangements and Migration Tendencies of 4-Methoxy-4-R-Cyclohexa-2,5-Dienones (R = Me, Et, COOEt) 7a, 7b, 7c

(A) In CF3COOH/CH3COOH

The methoxy-substituted dienones 7a» Z » and ]c^ all rearrange

with exclusive R group migration. The structure of the product from

7a was demonstrated by methylation of the phenol and comparison of

the product with the authentic compound , s^mthesized by another

48 route. The product was shown by GLPC and NMR comparisons to be

Page 50: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

43

48 different from 23 and _24.. The products from the rearrangement of

7b and 7£ were ascertained from spectra and analogy.

OCH

OCH.

22

OCH,

23

OCH/

24

OCH,

The kinetic results of rearrangements of 2a.» 2 » and ]c^ in 1:1

ratio (by volume) of CF3COOH/CH COOH at 25° are given in Table VI.

Evidence from NMR and UV spectroscopic studies show that the

rearranged products undergo further reactions to form dimers in the

acidic medium unless the system is rigorously protected from air.

This dimerization can be visualized by a color change (yellow). For

7c, the yellow color was noticeable after a few days although the

rearrangement was complete within 3 minutes. Monitoring the rearrange-

ment of ]h_ at \211 nm shows evidence of a further reaction, i.e.,

the absorbance increases (due to the formation of product) followed

by a second slower increase in OD at the end of the first reaction.

The product isolated from a reaction conducted under air, followed

by methylation, gave a raass spectrum which was identical to the

49 spectrum of _22 which was synthesized by a different route. This

dimerization was presumably caused by the reaction between the re-

arranged product and oxygen in the air, and can be avoided by monitor-

ing the reaction in an air-free cuvette.

Page 51: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

o m CM

4J CO

32 O O o

co ffi o o o o

ro

o c •H

co OJ C O C d) •H Q

O

co 4-1 c cu 6 (U 00 c CO >-( u a (U

M >

(U r-l X5

CO H

>^ o C <u

T3 C <u H

C o

•H 4-1 cO )-( ûO

•H s

r^ O rH

X

Csl .:^

r -O rH

X

co X3 o

aiá

c o

•H 4-t

a co 3 H O 00 U -H O S

co 4J c (U 3 4J •H 4J CO

X I 3

C/0

Td c 3 o Cu

e o o

X I .•

rO rH

XI

cO vO

• O CN

X I r\

<0 m m

• m

(U S

O (U

s r

<u

coj r^l

cO O C\l vO

cO O 00 r^

9 \

CM rH

cO O m •<r

*\ CO

4J w

o (U

s ^

4-1 H

- l r^l

o o o

n

r^ m

o o o

^ CO

1,1

7

o o o

M

258

4-1

w o o o

o <U s

M

4J

w o o o

l r^l

44

c LP

• C <u ûO o u u •H c

u <u

'Td c 3

4-1 3 o

T3 CU

•H V4 ^ cO o <u M <u :?

co C o

•H 4-1 O cO (U ct:

>

x i o

x: 4-1 (U

e e

•H (U x: c (U 00 ûû 3

O

<u x: 4J

>^ XJ

T3 CU 4J cd 3

rH cO > cu

co Jp :s co 4-1

c CO 4J CO c o O

(U 4J cO

ûá cO

Page 52: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

45

CH,

OCH

OCH/

OCH/

OCH/

_25

Again, the NMR method was used to estimate the protonation behavior

of dienones ]_, and was estimated £a_. 27% protonation for a. (and 7b) ,

and £3.. 22% for ]c^ in this acidic medium by the NMR method described

for dienones _5. These lower levels of protonation compared to those

for dienones _5 are presumably due to the inductive effect influence

of OCH3 and the lower acidity of the medium. Again, the difference

between ]a^ (or 7b) and 7£ is small, which is parallel to the protona-

tion behavior found for series _5 in CF3COOH.

These values were taken into account for calcualting k values and

the migration tendency thus obtained for M jj :M^ :M^^ = 1:620:57,000

for dienone ]_ in CF3COOH/CH3COOH.

(B) In Aqueous H SO^

The NMR and UV studies show that, as in the CF3COOH/CH3COOH

medium, the alkyl and carbethoxy groups migrate exclusively in aqueous

H/jSO, . The results for rearrangements of â* Zl > ^^^ Z£ ^^ 60.8%

H^SO, (by weight) at 25° are given in Table VII.

Compound ]c^ rearranges completely within 3 min, and no detectable

decarboxylation reaction occurs. This is presumably because the

Page 53: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

46

rearrangement of ]c^ is so fast in this acidic medium that it is

completed before the decarboxylation occurs.

Table VII. Rearrangements of Dienones ]_ in Aqueous H«SO

Compound

2- 4

Substituents Group k , X 10" obs ..

Migration sec

Ratio of

obs

Ta.

Tb

7c

Me, MeO

Et, MeO

COOEt, MeO

Me

Et

COOEt

4.3

1270

7850

1

295

1830

All products underwent dimerizations after the rearrangements

were over (in the open air) as in CF3COOH/CH3COOH medium. However,

since all three compounds rearrange faster than in CF3COOH/CH3COOH

medium, the dimerizations were detectable only long after the rearrange-

ments were over (especially for 7c). Therefore, no precaution was

made to avoid contact with air.

The protonation behavior of ]c^ in aqueous H^SO^ is not raeasurable

because of the rapid rate of rearrangement. Therefore only the ratio

of k , but not the migration tendency is given in Table VII. How-obs

ever, the k , ratio for 7a and 7b is equal to the migration tendency ' obs — —

of methyl:ethyl in this system since 7a and Tb have very similar

protonation behavior in any given medium. Note that the migration

tendency of ethyl (MI^, ) in this medium is approximately half as big CH3

3 as the one in CF COOH/CH3COOH medium.

Page 54: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

47

Because of the influence of the inductive effect by the methoxy

substituent (a^ = 0.25), lesser protonation for dienones ]_ than _5

was expected. Since the degree of the protonation of ]c^ can not be

measured, this correction to the migration tendency can not be made.

This value before the (1 + [B]/[BH ]) correction is 1830, as contrasted

„COOEt ' to M jj in CF3COOH which is 57,000. If the dienone is protonated to

a much lesser extent than the alkyl derivatives ]a_ and 7b in the

aqueous acid, which is intuitively reasonable, this correction could

be substantial. Still, to get reasonable agreement with the CF~COOH

data, the degree of the protonation of ]c_ in 61% H^SO, would have to

be less than 1%, which is surely too low. So the migration tendency

of COOEt in aqueous H^SO, is presumably much greater than 1830 but

substantially less than 57,000.

Rearrangements of 4-Methyl-4-R-Cyclo-hexadíenols (R=Me, Et, and COOEt) 8a 8b, 8c

The rearrangements of cyclohexadienols (8a, 8b, and 8c) were

carried out in dilute aqueous HCl buffer solutions because they

react too fast to be followed in a strongly acidic medium. Further,

the solubility of 8_b in aqueous HCl solutions is too low to allow

for accurate kinetic determinations, so some ethanol was added to

increase the solubility. Four sets of HCl solutions were prepared

by adding 40% (by volume) ethanol to aqueous HCl solutions. The

mixed solvents used have pH values (A) 1.83, (B) 2.03, (C) 2.11,

(D) 2.34 (y = 0.1, NAcl) as measured by a pH meter.

All three compounds show biphasic reaction when monitored at 259

Page 55: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

48

_ O O

nm (25 ) as described by Marx and Vitullo . Therefore, these dienols

first isomerized to their corresponding conjugated dienols 8J_

followed by slow rearrangement to the aromatic final products as

shown in Scheme XIII. The isomerization and rearrangement at 25

were treated as separable consecutive first-order reactions in each

case and the results are given in Table VIII on the following page.

From Table VIII, the ratios of observed rearrangement rate con-

stants of 8a:8b:8c were 1:11.8:0.003 for each condition. The ob-

served rate constants for isomerization reactions of these three

compounds were estimated in the weakest acidic solution (D) (pH =

2.34) and the results are also listed in Table VIII. Due to the

fact that isomerizations occurred too fast to follow by UV spectro-

scopy in strongly acidic buffers, no data were available in solutions

(A), (B), and (C). However, since the rates of rearrangement for

these three compounds enhanced (or decreased) proportionally in

different solvents, it is reasonable to assume that the ratios of

isomerization v^. rearrangement are the same in all these acidic

buffers.

The migration tendencies are not listed in Table VIII because

the concentration of the cations shown in Scheme XIII are unknown,

and the ratio of ethyl rs. methyl migration for is unknown. An

attempt to measure this via deuterium-labelling is in progress. In

8c, COOEt migrates exclusively.

In the methyl and ethyl substituted dienone 2 » the migration

tendency of ethyl (M^^ = 50) seems to reflect the ratio of methyl

and ethyl migration products (2% methyl migration and 98% ethyl

Page 56: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

o m c

4J cO

CO

c o

• H 4-1 3

r-l

o C/3 O

• H

• H O

<d

00 1

Cfl r - l O

c (U

• H Q

co 4J C cu B (U 00 c CO u u CO (U

»3

>

CU

r H X 5 cO H

<H o

o TA

U

s

/~\ Q •s^ /

C o

•H 4-1 3

T-\

o W

co X3 o

aií!

00 r H

• CM

II

tc a

49

0 0

CO o o

CM CO

O

c o

o

CN

II

ffi

1

o r H

X

o

CN 1

o

X

o

co O 1-i

X

m <y\

r H

1 o r H

X

r- l

o

>^ 1 o 1-i

-û X

CO

0 > CM <y\

co I

CN I I

X

o CM

X

o <r

X

o

co

PQ

C o

• H 4J 3

r-l

o C/3

co o CN

CO I I

vO I

X

CN

o Cv4

X

0 0 CO

• Csl

X

co co

\o

C o 4-1 3

>H O co

< 0 0 |

TS c cO

« '^l ooj

M

C0| oo| u O

<H

CO 4J

c cO 4J Cfl C o o <u 4-1 CO u c o

•H 4-1 CO N

•H U (U

s o cn

•H

•73 CU > U <u CO

X3 o

• <u u 3 co cO (U S

o 4J

3 o

r H

co 0 o 4-1

co cO 5 (U 4J cO U

4-1

c (U

s <U 00 C <0 u u CO (U u

<u x: H

cO

Page 57: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

50

migration). It was also found that pinacol lOb shows the same result

Et (M = 54; methyl migration £a.. 2%, ethyl migration £a.. 94%; this

will be discussed later) in H^SO,/HOAc/H^O media. Thus, it is

reasonable to predict that ca. 4.5% of the k , value in 8b (see

— obs —

Table VIII) was contributed by methyl migration if one assumes 8a

+ 28 and 8b exist in a similar concentration in a given acid. Thus k = 0.955 k , . Taking this value into consideration and the p obs

Et statistical value of 2 for 8a, M value of 21.1 may be calculated

— CH3

for this system.

CH, R

• ^

-1

CH/

•^ I

-2

R H

OH

8

8 8'

R = CH , ; R Co^r, 8b, R = COOEt, 8£

Scheme XIII

Unfortunately, the concentration of 8__ can not be measured.

Therefore the value of M^^^^ could not be obtained quantitatively.

However, an estimated value of 0.003 <\^ ^l ^^^ made based on the

Page 58: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

51

^obs ^1^^^» although the real value is yet unknown. This estimated

COOEt value is smaller than the M values in the other systems studied

Et (_5 and 7_) . Note that the M ^ value (21.1) is also smaller than in

the _5 and "]_ series.

From the spectral parameters published for 5,5-dimethyl-l,3-

cyclohexadiene (X = 257 nm, e 43000) which were used as a model max max

for the chromophore, the equilibrium constant for 8c'/8c is estimated

to be 0.65 independent of pH. This value is similar to the value of

8a'/8a (= 0.60) in dilute acidic buffers.^^

The isomerization reaction of the dienols 8_ to the conjugated

dienols 8J_ gives a further clue as to the magnitude of the migration

tendency of the ester group. In all cases, this isomerization reac-

tion was faster than the rate of rearrangement. The ratio of k. isoraeriza-

^. /k ^ calculated from the data in Table VIII is 8a = 30, tion rearrangement — ^ = 10, and 8c = 48.

These data demonstrate that the migration step is rate determining 23

(which was more rigorously demonstrated by Vitullo for 8a), since

the carbonium ion intermediate is partioned between isomerization

(k_), which is reversible, and the slower rate of rearrangement (k ),

which is irreversible. Although the rate of formation of the carbonium

ion is depressed for 8c_ by an unknown amount due to the inductive

effect of the carbethoxy group, the ratios of isomerization to re-

arrangement in the cations 8a and 8c is almost the same (30 v£. 48) .

This suggests that the slower rearrangement of 8£ is due almost

completely to the ionization step k.. and the migration tendency

,,C00Et . 1 M is close to unity. CH3

Page 59: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

52

Reactions of 4-Methoxy Cyclohexadienols (9)

Instead of rearrangement, 4-methoxy cyclohexadienols (9) undergo

decomposition to para-substituted phenols in dilute acidic solutions

(A), (C), and (E) (solution (E), pH = 1.27 aqueous HCl, u = 0.1,

NaCl) according to NMR and UV analysis. The decomposition rates of

9a and were very similar [t .,. ca . 60 sec in solution (A) and (C) ],

and was much slower (estimated to require 5 days for completion

in aqueous HCl, pH = 0.66). However, the decomposition of was

complete within 2 minutes in CF-COOH. The decomposition may be

R

H" , -CH OH 3

\ <

H OH

+ CH3OH

9*

9a., R = CH3; fb, R = C^H^

concerted instead of going through the cation, since an a-cation

19 23 adjacent to COOEt is very destabilized. * Since cation 9* (R =

CH3 or C^H^) is more stable than 9^, the latter presumably does not

form to an appreciable extent.

Page 60: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

53

Rearrangements of Pinacols (lOa, lOb, and lOc)

(A) In CF3COOH/CH COOH

For compounds lOa and lOb, both alkyl and phenyl groups migrate;

for lOc, COOEt migrates exclusively according to NMR spectroscopy.

Compounds lOb and lOc follow pseudo-first-order kinetics. However,

the log (A^ - A) ATS. time plot of lOa exhibits a break line with an

overall concave upward shape (see Fig. 1). The k , values were ca.

obs — -3 -1

3.98 X 10 sec for the first part of the reaction, and £a. 1.90 x -4 -1 o

10 sec for the second part at 25 . The results are given in

Table IX.

The ratio of phenyl v;s. methyl migration for lOa was determined

by the method of Schubert. Thus, the authentic phenyl and methyl.

migration products, a,a-dimethylpropiophenone (26) and 3,3-diphenyl-

butanone (27), were prepared and the molar absorptivities at different

wavelengths were recorded. Then equation 4 was applied to cal-

culate this rate, which was essentially constant when measured at

different wavelengths (see Table X).

Ph CH_ , Ph Ph

1 I 3 Ph ^ I ^CH Ph — C — C — CH„ > X — C — CH„ + Ph C C^ 1 I 3 O^ ' ^ > "^O

OH OH ^ CH3 CH3

lOa 26 27

Ih ^ _Hî_= ^" " ""Me _ _ (Eq, 4)

^ Me e„, - e

Ph 00

Page 61: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

54

0 4

Figure 1.

8 12 16 20 time (min) ,

Plot of log (Aoo -A) vs. time for iOa in CF^COOH/ CH COOH at 25°

Page 62: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

o m CM

cO

O O O

co ffi

o DC o o o

co W O

c •H

Cfl r-l o o cO

c .H ru <H

o Cfl 4-1 c <u B <u 00 c cO

u u cO <U

pci

<U

X3 CO

H

U J

o

o a •H M 4-1 CO (^

sO

o T-\ r-{

1

X o <u û . Cfl

..bíJ

vO

o r-{

X r H 1

Cfl o X I <u O cfl

^

0 0

c • H 4-> CO M 00

• H

S O, 3 o u o

CO 4-> C cu 3 4J . H 4J CO

a O

3 C/3

X ) C 3 o a S o o

CO r- l

O 0\

cO O CO vO M

CO

o 0 0 (J^ CO

/—s ^s 0 0 r- l N ^

x: pu

^ / - s &•« CN 0 0 ^ w '

T 3 m

• 0 0

T3 O CM 0 0

CO

o o

• o

• cOJ C J |

0 0 •

<r

«% CO

-o / - s O O O o^ r >.

0 0 •

<r

,-\ r H

M

/ ^ ô S -d-CT\ N w

4J W

.< /—\ ^ S r- l

• cO o

'—/ 1 '^

^s m 4J w [xl

CO CO O PC O

X! P H

aC

o

aC (1H

co *» 33 o

0\

4J

w «\

aC O PL, O

x: p

M

4J

w o o o

M

CO co co K o

cO O r H

ffi o

a O O r H

ffl o

o o r- l

55

• cO

O r-i

U

o <H

4J U cO a 4J CO

u . H <H

(U

x: 4J

MJ o

C - i <

CO O r- l

!-l

o <H

4J U cO D .

73 C O O <U co

<U

x: 4J

"H O

0 CO 3 X3 D 0

CO

w a

co

Page 63: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

56

Table X. Product Ratio of 10 in CF3COOH/CH3COOH.

262.5

265

267.5

270

6160

5480

4940

4290

610

590

562

468

1548

1490

1361

1206

0.203

0.225

0.223

0.239

ave. 0.22 + 0.01. ^ e„,_ and e„ values from Schubert's publication; — Ph Me

51

e , is the molar absorptivity of 26, and e., is the molar absorptivity ph — Me

of 27. e is the molar absorptivity of glycol solution after raore — 00

than ten half-lives of reaction.

The average [Ph]/[Me] value thus obtained was 0.22 + 0.01. The

partial rate constant for methyl migration (k ^) was then calculated

by taking this ratio and the statistical factor the number of methyl

groups (a factor of 2) into account.

For lOb, the product ratio was determined by NMR spectroscopy.

The NMR spectrum of the total product mixture from lOb after at

least ten half-lives of reaction time shows mostly ethyl migration

product (8.) (see Fig. 2 on the following page) . In order to sort

out the percentages of the methyl and phenyl migration products,

TM the NMR shift reagent, Resolve Al EuFOD , was added gradually to

give the spectrum shown in Fig 3. It was concluded that the singlet

which shifted to ô 3.12 was the methyl signal of the phenyl migration

Page 64: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

57

o o o CO

PC

o ffi o o o

CO w o c

•H

X3

o o <U S-l 3 4J

X •H

O 3

T3 O U O.

4-(

o N

o \ 0

6 3 U u o (U

co

CN

(U !-i 3 00

•H

Page 65: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

- o

58

! O

O

o

2

_o .

L-

o

o eo

_J O

ffi O O

o co ffi

o ffl o o o

co w o c

•H X) O

c (U

s <U 00

c cO U

u cO (U

s o u

IH <U ?-( 3 4J X

•H

S 4J

o 3 o !-( a o

Nl

o o

S 3 5-1 4J O CU

Cfl

CO

(U J-i 3 00

•H

T3 CU

T3 ' d cO

co cO 15

s H Q

O W 3 W

CU >

r-l o co (U

4J C cu 00 cO cu >-l +J M-l • H

co

<u x : 4J 5-1 <U 4J <H cO

Page 66: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

59

product (2^); the singlet at 6 3.62 was the methyl peak of the methyl

migration product (_30) ; and the big singlet at ô 6.43 was the methyl

peak of the ethyl migration product (28) . Therefore, integration

of these three singlets gave the ratio of CH^^Et^Ph migration of

lOb as ca. 1:94:5.

Ph CH,- Ph CH I I 3 , CH Ph^^3

Ph — C — C — Et > ph — C — C^ + > C — C -- Et • I I ^O O ^ OH OH Et ^ ^ Ph lOb 28^ ^

I ^^ + Ph — C — C^

I ^ O CH3

30

The break line of the log (A - A) v_s. time plot and the incon-

sistency of ratio of k , and the product ratio indicate a mechanistic

change which will be discussed in detail in the Discussion section.

The COOEt group migrates exclusively for lOc according to NMR

COOEt spectroscopy. Thus, the k value is the same as k , . This is

rationalized by the stability of the cations 21 ^ ^ 2 ^ which result

from dehydration of different OH groups of pinacols 10.

Ph R Ph R I I I I

Ph — C — C — CH, Ph — C — C — CH + I 3 1 ^ 3

OH OH

31 32

a, R CH3; b, R C^H^; c, R COOEt

Page 67: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

60

Cation 21 is more stable than i since the positive charge is

on the benzylic position. This cation can give the R or CH migration

product. Especially when R = COOEt, this substituent destabilizes

cation 22£ greatly and therefore COOEt migration is the only pro-

cess. When R = methyl or ethyl, cations 22a and 22b are reasonably

stable, so that phenyl migration occurs too.

(B) In Aqueous H SO,/HOAc

The results of rearrangements of series : (except lOc) in solu-

tion (F) (H^SO^-HOAc-H^O, 45.0:17.0:38.0) at 25° are given in Table

XI.

For lOa, both methyl and phenyl groups migrate to yield TJ^ and

26, and the ratio of the products is determined by the method of

Schubert as phenyl/methyl migration = 0.135 + 0.005. This has been

taken into account to calculate k 3 in Table XI. P

For lOb, the product ratio was determined by the NMR method as

described previously. Fig. 4 (as shown on the next page) was ob-

tained after several small additions of the NMR shift reagent.

There was then found ££. 2% methyl migration products (30), 93%

ethyl migration product (28), and 5% phenyl migration product (29)

in solution (F).

An unknown amount of decarboxylation occurred in competition

with the rearrangement for lOc. Therefore no experimental data are

available for the rearrangement. However, the total reaction was —6 —1

slow and a maximal value of k , ca. 10 sec was estimated. The obs —

rearrangement reaction is slower than this by an unknown amount.

Page 68: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

• 0 m CM

4 J

cO

O CN

1 O < O

1 <r

O C/5

CN p::

c •H

/ . — V

O rH ">—/

<0 rH o o cO c •H

PH

>H O

CO 4 J

c (U

s (U 00

c cO M >-( CO (U

• (H X

<u r-i X> CO H

>. O

c <u

'T3 C CU H

C O

•H 4 J

CO IJ 00

•H

s

<r o rH

X CX,

,i<!

•<r o r-{

X

CO X I O

r ^

c O •H 4 J cO >-i 00

•H

S CX, 3 O í-i o

CO 4 J

c (U 3 4J •H 4 J Cfl

X) 3

co

T3 C 3 O P-S O o

o rH

cO

00 •

co

\D "O

• r^

&^ r g r - ( v»-/

x: p-,

»

s-s 00 00 >.—/

o -cr m

X5 CM 00 rH

V Û CJ rH

»v

fr-S co CTi v ^

4J

w A

/ — N

^S CN

a

cO o

, — N

&-? W LO

V — /

co co PC o

rC p->

#v

ffi x: O PL,

x: p-i

CO ffi o

«s

4J w

»> CO CO

ffi o

cO o r-l

p:í o

X3

o rH

>. ;.., (U >

cu ,o

O 4J

T3 <U

s D U)

ich is

as

i

x: :$

u o

•H >

eha'

X I

c O

•H 4J cO C O

4 J

0 >-l

(U x: 4J

u o

< H

'O <u 4 J

o (U }-l

u o o

4 J

o c <u M cO

co cu 3

rH CO >

o

4J w cx

.i»i

X3

CO

O Cla . ^

tO

• X I o r-l

X3 C CO

tO O r-l

U O

<H

U cO

r-l •H

s •H co

61

Page 69: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

62

o X I o < o X

I •<r

o C/D

CM

X

XI

o

4J c <u 6 (U 00 c cO u u cO <U 5-1

E o !-i

>H

<u !-i 3 4J X

•H

s 4J O 3

O U

a

N

o o

S 3 5-1 4J O <U Cl. co

T3 (U

n3 Tí

cO

co cO

s H O

O w 3 W

(U >

rH O co <u

4J

c (U 0 0 cO (U 5-1

CD

n (U x: 4J

S-i (U

CO

cu 5-1 3 00

•H W

Page 70: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

63

The rearrangement step was proved to be the rate determining

step for lOa (and presumably also lOb). Therefore, a comparison

CHo Ft- Ft* of k 3 and k gives directly the M... value (= 53) , assuming the

P P CH3 Et

protonation behavior of lOa and lOb is similar. This M value is

similar (within experimental error) to the product ratio (the ethyl

migration product 28/methyl migration product _30 = ££. 50) . This

supports the assumption thst the rearrangement step of lOb is also

the rate-determining step.

Summary

A summary of the migration tendencies of methyl, ethyl, and

carbethoxy grups (if available) in each system are given in Table

XII.

Page 71: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

Table XII. Summary of Migration Tendencies.

64

Series Rearrangement Conditions

CF3COOH (25°)

CF3COOH (45°)

Aqueous H.SO, solutions

1:1 CF3COOH/CH3COOH

Aqueous H,^SO, solution

M CH3 CH,.

1

1

1

1

1

M Et CH,

103

98

49

620

295

M COOEt CH/,

24.7

23.4 i

ca. 10

57,000

57,000'

8

10

HCl buffer solutions (A), (B), (C), and (D) (pH= 1.83-2.34

Solution (F): H_SO,:HOAc: H^O 2 " 45.0:17.0:38.0

21.1

53

a

These values are estimates, due to the difficulties in measuring the protonation behavior. See the text.

'only decarboxylation takes place. In CF3COOH/CH3COOH, the rearrange-ment step is not rate determining.

Page 72: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

CHAPTER III

DISCUSSION

General

In all systems investigated to date (except series 9_ which

eliminates CH3OH instead), the kinetic study gives the observed rate

of the rearrangement (k^^g). The k ^ value in a given acid depends

on: (i) the concentration of cation, which is related to the term

[BJ/ [BH J; (ii) its propensity to rearrange. This latter factor

depends on both the inherent reactivity of the cation as controlled

28 by its substitution pattern, and on the medium.

One of the purposes of this study was to determine the migration

tendencies of methyl, ethyl, and carbethoxy in various rearrangement

systems and in different solvents. The experimental data give only

k , . In order to calculate the rate constant for the rearrangement ODS ° step k-, data to satisfy equation 1, k_ = k , (1 + [B]/[BH ]), has

2 ^ 2 obs

to be obtained. In the case of the dienones, data on [B]/[BH ] are

calculated from the protonation behavior of each compound or could

28 52 be obtained from the literature. ' Unfortunately, in the pinacol

and dienol systems, more complex expressions are required, and the

complete kinetic analysis would be required which is impossible be-

cause of decarboxylations and other competing reactions. Estimations

of the limits for the values of migration tendencies were made.

Rate liminations are also set by kinetics which are either too

slow or too fast to be measured accurately by UV spectroscopy.

Therefore, changes of the solvent acidity to adjust the rearrangement

rates to a measurable range in the same series is necessary.

65

Page 73: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

66

The data for migration tendencies will now be discussed in

detail in the following sections, looking into the electronic effects

of the migrating groups, solvent and temperature effects, ideas on

transition state structure, and most importantly, an investigation

Et of the question of whether the M value be used as a probe for the

CHo

transition state charge density in a given reaction.

Electronic Factor in Each System

Is an electronic effect the raajor factor which determines the

migration tendency in the systems studied?

There is little doubt for dienones (_5 and 7_) that the answer

is positive for the following reasons:

(i) Protonation gives an ion which is stable enough to observe

by spectroscopy before it rearranges, and there are no complications

due to a leaving group;

53 (ii) The dienone ring is planar and the two groups at position

4 are in the same uncrowded steric environment;

(iii) The charge density at the migration terminus before the

. 21c. rearrangement is very high (estimated by NMR as 0.15 unit ),

suggesting that the reaction is controlled primarily by electronic

and not steric factors.

The dienol-benzene rearrangement (8 and _9) is a reaction which

is formally similar to the dienone-phenol rearrangement. Even though

this reaction is complicated by the departure of the leaving group

(which is H O" in aqueous HCl medium) and an isomerization reaction

which occurs before the rearrangement step, the migration tendency is

Page 74: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

67

determined by the rearrangement step only. Vitullo had shown that

rearrangement is the rate-determining step, and the transition state

of the rearrangement has substantial carbonium ion character.

Therefore, it is concluded that the electronic factors dominate in

the transition state.

The pinacolic system is more complicated. It has been pointed

26b ^ out that the ratio of the products from migration of R or R'

can also depend on the stereochemistry and on rates of rotation about

OH I OH 1 OH I I > I I 1 1

R — C — C — ^ R'_-C — C — + R — C — C —

l' - - l - l' the central C—C bond relative to rearrangement. A further problem

is that a group R may migrate in preference to R', not because R

is intrinsically a better migrating group but because the R' left

behind may be better able to stabilize the product cation. All in

all, steric factors can play a crucial role in this system. The

system studied was designed to cancel out the steric component.

Placing two phenyl groups at the migration termini allows the

groups R and R' to be in similar environments. Also, the migration

tendency measures the rearrangement in an intermolecular sense, so

the effects of most possible variables are cancelled out. Further,

Schubert has shown that the process from glycol lOa to the transi-

tion state for rearrangement follows the H acidity function, and that

is.

0 exchange occurs at the benzhydryl oxygen in 0 enriched solvent (the solvent he used was H SO,/HOAc/H^O).

Page 75: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

68

This, combined with the stabilizing influence of the phenyl

substituents on the classical carbonium ion (33) before the rearrange-

ment, suggest that a substantial charge density is involved in the

transition state in H^SO^/HOAc/H^O solution [solution (F)]. However,

the failure to observe pseudo-first-order kinetica for rearrangement

of lOa in CF3COOH/CH3COOH suggests a mechanistic change and requires

a more detailed discussion.

R Ph \

^ C C R' I +^Ph

OH

33

Change in Rate-Determining Step for Rearrangement of Pinacols 10 in CF3COOH/CH3COOH

In order to understand what actually occurs for series _10 in

the CF^COOH/CH-COOH medium, three corresponding epoxides (34a, 34b,

60 and 34c) were prepared and kinetic data were obtained by UV

spectroscopy under the same conditions as for series J^ (1:1 ratio

of CF0COOH/CH3COOH, 25°). The reactions of 3Ji_ in acidic medium

are shown in Scheme XIV.

Note that in Scheme XIV ring-opening of 3^ generates the same

cations (10 ) as the pinacols lO^ do in acidic medium, and the re lease

of the s t r a i n for the three-member ring enhances the ionization r a t e

f or _34_. The ionizat ion i s e ssen t ia l ly an i r r eve r s ib l e process because

i t i s highly unfavorable to regenerate 34 from the s tab le ion 10 .

Page 76: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

69

H+ \ /CH3 l> P . CH3 %fO,

^ C ^ - y C ^ ^ Ph - C - Í - ^ > Ph - C - C - R +

P^ 0 R OH ^...3 CF.3C-O OH 3II

34 10

0 + 35

^2

ph CH3

Ph — c — c I \ « R 0

a , R = CH3; b , R = C^H^; c, R = COOEt.

Scheme XIV

For 34a, a very f a s t r a t e was observed for approximately the f i r s t

half of t h e r e a c t i o n , followed by a much slower r a t e when the forma-

t ion of t he product 36a was monitored. The r a t e cons tant for the f i r s t

pa r t of t he rearrangement i s too f a s t to follow by UV spectroscopy.

-4 However, t he slower r a t e cons tan t i s est imated to be £a.. 1.86 x 10

sec . C l ea r ly , the ca t ion lOa p a r t i a l l y rear ranges to 36a, and i s

p a r t i a l l y t rapped by CF3COO (k^) followed by r e i o n i z a t i o n (k _) of

the t r i f l u o r o a c e t a t e (35a) through ca t ion 10a which can then rea r range

to 36a. Thus, k_3 i s the r a t e determining s t e p for t he l a t t e r pa r t of

the r e a c t i o n . Since the ca t ion 10 i s formed i r r e v e r s i b l y from 34,

k^ must be comparable in s i z e to k/., and both a re f a s t e r than k, ,

which i s thus r a t e de termining .

For 34b, the rearrangement i s complete in seconds. Therefore , no

k i n e t i c d a t a a re given and k , i s es t imated to be bigger than 10 obs

Page 77: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

70

sec . This i s r a t i o n a l i z e d in t h a t e thy l i s i n h e r e n t l y a much

b e t t e r migra t ing group than methyl (product a n a l y s i s of lOb sugges ts

t h a t e t h y l i s approximately 94 t imes f a s t e r in migra t ion as compared

to methyl in t h i s system in a CF3COOH/CH3COOH medium) and the

migra t ion i s complete before the CF-jCOO spec ies can r eac t with ca t ion

lOb . Thus, k, i s r a t e de te rmining .

-3 - 1 For 34c (R = COOEt) , the k ,_ va lue i s 4.62 x 10 sec . The

obs

UV and NMR spec t roscop ic da ta suggest tha t t he i o n i z a t i o n (k , ) i s the

r a t e -de t e rmin ing s t ep ( r . d . s . ) and again , no d e t e c t a b l e amount of

t r i f l u o r o a c e t a t e 35c was found. This provides evidence t ha t COOEt i s

a b e t t e r migra t ing group than methyl but the exact migra t ion tendency

i s unknown. Note t h a t k. i s depressed , as compared to the va lues of

34a and 34b ( too f a s t to measure, >10 ) , by t he induc t ive ef fec t of

the e s t e r group.

Applying t h i s da t a to the p inaco l c a se , the mechanisra of _10 in

CF3COOH/CH3COOH can be w r i t t e n as shown in Scherae XV.

Ph CH_

1 1 ^ c — c — 1 i OH OH

R

H+

Ph

Ph

Ph 1 1 C 1 R

Ph 1 C -+

10+

> /

CH/. 1 3

— C — 1 OH

• 2

CH3

' ^ o

R

CF3COO"

^3 .

~ ^ 3

Ph 1

Ph — C —

CF3 1

C-0

u 11

CH_ 1 3 C — 1 OH

R

11 ., R = CH3; b , R = C^H^; c , R = COOEt.

Scherae XV

Page 78: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

71

For lOa, the rate constant (3.98 x 10~ sec"''") observed for the

first part of the reaction is essentially the ionization step (k..) ,

and the following slower rate (k , = 1.90 x 10~ ) is identical to

obs

the slow one observed for 34a (= 1.86 x 10 sec ) and i s there -

fore k_3 for the ionizat ion of 3 5a. This i s to say, the rearrange-

ment of the methyl group i s slow enough to allow the CF COO~ species

to react with lOa . For lOb, pseudo-f i rs t -order k ine t ics were observed (k , = 1 . 9 6

obs -2 -1

X 10 sec ) . This must be due to the ionization of lOb (k,) . Again,

no trifluoroacetate 3 5b was observed. Note that in this system the

ionization is irreversible because this reaction was carried out in

CF3COOH/CH3COOH medium and the water concentration is negligible.

Thus the pinacol system _10 parallels the epoxide system 3j4, except

that k, is about two order of magnitude faster for the epoxides.

— 6 — 1 For lOc, k , was 4.80 x 10 sec . Again this is a measure

obs

of k , which is slowed down by the inductive effect of the ester

group.

From the discussion presented above, it is conciuded that the

migration tendencies follow the order that Et^COOEt^CH^, with the

M-.Í value ca. 94 times bigger than ^ ^ „ ^ , as judged by the product Cn3 L.n.3

ratio of Et to Me migration in compound lOb. Since in no case is

the r.d.s. the rearrangement, it is impossible to determine migra-

tion tendencies for this system in CF3COOH/CH3COOH.

Page 79: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

72

T r a n s i t i o n S t a t e s for Dienone and Dienol Rearrangement

In e i t h e r t he rearrangements of t he dienones (_5 and _7) or the

d i e n o l s (8^ and 9_) , one can r ep re sen t the rearrangeraent s tep in shown

in Equation 3 :

Eq. 3

The group R" at position 1 is in conjugation with the charge

at the initiation of the migration step and the group R' at position

4 (the migration origin) is in conjugation at the termination of the

migration step. Thus, the position of the transition step should

vary with the nature of the group R' and R", according to the

54 Hammond postulate, in the following way. In dienones , in which

R' = Me and R" = OH, the migration is an endothermic step, so the

transition state should be product-like. In dienones ]_, in which

R' = MeO and R" = OH, the transition step should be central. In

dienol 8, in which R' = Me, R" = H, the reaction is exothermic, so

the transition step should be more reactant-like. Dienols 9_ (R' =

MeO, R" = H) should give an even more reactant-like transition

state. Unfortunately, they decompose instead of rearrange. Thus,

the amount of charge necessary to be stabilized by the migrat.ing groups

R should vary considerably, and the behavior of these series of

compounds should show a nice trend in migration tendencies. The

Page 80: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

73

reac t ion of dienols 8 are complicated by the ambiguities connected

with having a leaving group (H^O ) to draw off some of the charge

dens i ty , but presumably the highly resonance-stabil ized ions formed

are f a i r l y free before rearrangement occurs. The migration step

has been determined to be rate-determining in the dienol-benzene

23 rearrangement, so comparison of ra tes is va l id .

The t r a n s i t i o n s t a t e s (T.S.) for these rearrangements are

shows as below:

c - ' "R

T.S. 5 T.S. 7 T.S. 8

Tool of Increasing Electron Demand

It is generally accepted that the importance of neighboring

double bond participation should diminish as an incipient cationic

cc tZíl

center i s s t ab i l i zed by s t ruc tu ra l modification. H. C. Brown

termed th i s as the "tool of increasing electron demand". I t i s

now supported by a great deal of data. However, the or iginal study

by Gassman and Fentiman on the anti-7-norbornenyl system pro-

vides one of the best examples for the present case.

Thus, these authors observed that the ra te enhancement by the

double bond of 10 observed in the parent secondary system decreases

with the introduction of s t ab i l i z ing groups at the 7-position (38)

Page 81: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

74

and effectively vanished with the -anisyl group.

OPNB

Z = 7-H 3,5-(CF ) £-CF 2-H ^-CH^O

1.00 1.00 1.00 1.00 1.00

OPNB

PNB = £-nitrobenzoate

38

11 10 255,000 34,000

41.5 3.4

8.0-1

4.0 ..

log ( z)

0.0

4.0-

8.0"

"^ " o-OCH

E-CF^-^

3,5-(CF3)2-^

-2.0 -1.0 0.0 1.0

Figure 5. p-a"*" plot of 21 and on 70% aqueous dioxane at 25 C,

Page 82: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

75

+ The r e a c t i o n cons tan t p , from the r e l a t i o n s h i p , log (k /k^) =

+ + 57 ^

P C7 , p rov ides a convenient measure of the e f f e c t . The p va lue

for 37_ i s - 5 . 2 7 ; for 38 i s - 2 . 3 0 . With a s u b s t i t u e n t even more

s t a b i l i z i n g than ^-OCH^, namely, ^p^-N^CH^)^, the behavior of 2 1

p a r a l l e l s 3_Z. ( see F ig . 5 ) .

This example demonstrates that with a stabilizing group (i.e.,

-OCH3) present in the substituent the demand for extra electron

density is less, and the positive charge is well-delocalized by the

substituent.

Applying this concept to the present case, the amount of

positive charge density which accumulates on the migrating substi-

tuent for the transition state is decreased in the order T.S. Z. _5>2.

T.S. _7, presumably being about central on the reaction coordinate for

the rearrangement of series Z» evidently requires the most charge

stabilization by the migrating substituent, since neither oxygen

atom can stabilize the charge as well as it could in a less central

transition state.

Et M^„ Value as a Probe

Et Does the M value for each system reflect this trend? Is the

proposed postulate valid?

Et The results suggest the answer is positive. The M value

(at 25°) in CF3COOH (and CF3COOH/CH3COOH) of 1_ (= 620) >_5 (= 103);

and in aqueous H^SO^ ]_ (= 295) >2 (= 50) >_8 (= 21.1).

The values in ]_ are much greater than have been observed for

ethyl migration in any other system to date.

Page 83: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

76

Ft-The second question is, can the H^^ value used as a probe to

COOEt predict the M ^ value in the same system?

In CF3COOH (or CF3COOH/CH3COOH) medium, the data suggest it is

valid. Thus, when M^^^ = 103, M ^ * is £a. 25 for dienones ; when

Et COOFi" ^CHo " ^^^' CH ^ 57,000 for dienones ]_. This means, when the

migration tendency of ethyl is small, migration tendency of carbethoxy

is small; and vice versa. Again, the value for M^„ in series 7 is CH3 —

much greater than for any other system studied to date.

In aqueous acidic medium this trend seems valid too, although the

data are clouded somewhat by the inability to measure the protonation

COOEt behavior, so that the exact vaiue of M -j is unknown (see Table

L.tl3

XII in Results section).

An interesting comparison was made between the dienone _5 and

Et the pinacol 10. Thus, the M^„ value is 50 for 5, and 53 for 10 in

L.n.T —

aqueous H_SO,. These vaiues are very similar, which suggests that

the transition states for the rearrangement step in these two systems

accumulate similar amount of charge density, according to the

postulate that was pointed out in the Introduction section (see page COOFt

19). Thus, the prediction is made that the M in series 10 CH3

should be similar to the value found (25) for series _5 in CF3COOH.

However, in lOc, the initial rate of ionization of the pinacol will

be depressed an unknown amount by the inductive effect of the COOEt

in the 3-position. More seriously, the rate-determining step appears

to be this ionization, not the rearrangement step. At least the

qualitative finding that the M^„ values follow the order Me<COOEt<Et CH3

is in agreement with this idea. In aqueous acid, only decarboxyla-

Page 84: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

77

tion occurs, so no conclusions afe possible.

Temperature and Solvent Effects

The reason dienones _5 were chosen to investigate the temperature

effect is simply because these three dienones have observed rate

constants which are closer to.each other than the other series, so

more variation is possible to keep all rate constants within the

experimentally accessible range. The data (see Table II) show that

at the higher temperature (45°) the M,,„ and M .. ^ values are some-L.n3 L.n3

what smaller. However, it is too risky to jump to any conclusion

based on this tiny change, especially in view of the small temperature

change (AT = 20 ). Therefore, it is concluded that the migration

tendency is essentially constant with respect to the temperature

over the accessible range. Et

As raentioned before, the M . values in dienones 5 and 7 are CH3 - - .

approximately doubled in CF3COOH as compared to those in aqueous

H_SO,. This seeras to suggest that the soivent has similar influence

on migration tendency in both systems. Again, a factor of 2 is

considered a small change and it is hard to draw any certain con-

clusion. It seems that the migration tendency is somewhat "inert"

to the identity of the solvent. Presumably this is largely because

the cations studied are so delocalized that external influences are

minimized.

Carbethoxy As A Migration Group

One may speculate why the COOEt group undergoes such varying

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78

relative rates in different rearranging systems. This seems reasonable

when one considers that it has an adjacent Tr-bond and the electrons,

though not polarized ideally, are highly polarizable and can supply

substantial electron density on demand to stabilize positive charge

58 density in the transition state. The transition state for COOEt

migration presumably looks a lot like structure 21» with 40 being

a major resonance contributor and structure 4 ^ being a rainor con-

tributor. In fact, instead of rearrangeraent, fragraentation via an

1- . . . 59,19 acylium lon occurs m extreme cases.

Ov /OEt oX /OEt 0+ OEt

%-^ ^c^ \c/ r. c^ ^C = C ^ ^C —

39 40 41

Page 86: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

CHAPTER IV

CONCLUSION

In general, the rearrangement systems investigated to date exhibit

a nice trend, such that when the migration tendency of ethyl group is

small, COOEt acts as a very poor migrating group; and vice versa. The

range of relative rates of COOEt group migration is surprisingly wide

in these systems, presumably due to the fact that the ir bond of the

carbonyl group back-donates some electron density to the transition

state of the migration. The relative migration rates of methyl and

ethyl groups show a wide but lesser difference.

The migration tendency is essentially independent of solvent and

temperature effects over the rather small range that could be studied.

Therefore, it appears to reflect the migrating system.

From consideration of the structure of the transition state and

the Gassman and Fentiman approach, the data suggest that the postulate

proposed that "the more positive charge density that is required to

be stabilized in the transition state, the better an ethyl group

should be in migrating as compared to a methyl group" is valid, at

least for the systems studied. Further, data also suggest that one

Et might use M_.. values to predict, at ieast qualitatively, the migra-

CH3

tion tendency of the COOEt group in other systems.

The carbethoxy group decarboxylates extensively in strong aqueous

acidic media and thus makes it difficult to determine the migration

tendency in a rearrangement reaction. Combining this with the fact

that the dienone system is one of the best to determine the rearrange-

ment rates without complicating factors, it is suggested to use some

79

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80

electronegative groups which are more stable to acidic media (such

as ketone, cyano, etc.) as substituents in the dienone systems for

further study.

Page 88: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

CHAPTER V

EXPERIMENTAL

G e n e r a l

A l l r o u t i n e NMR s p e c t r a were run on a Var ian A-60 or XL-100

s p e c t r o m e t e r i n CDCI3 s o l u t i o n s u n l e s s o t h e r w i s e s t a t e d . A l l NMR

chemica l s h i f t s a r e r e p o r t e d in ô u n i t s downfie ld from i n t e r n a l fTTW

reference TMS. Infrared spectra were obtained with a Beckman AccuLab

8 as a thin film or in CHCI3 solution. All melting points are un-

corrected and were determined after at least one recrystalization

and drying at 0.1 mm Hg. Melting points were obtained in open

capillaries on a Laboratory Device's "Mel-Temp." Silica gel, 60-200

mesh, frora Aldrich, were used for all column chromatography. Columns

were packed as a slurry using the first eluting solvent as the packing

solvent. Unless otherwise stated, when reactions were worked up

using an organic-aqueous separation, the organic layer, after extrac-

tion with appropriate aqueous solutions, was dired over anhydrous MgSO^

for a few minutes, then filtered and the organic solvent(s) removed

with a Buchi Rotavapor-R with water aspirator vacuum of 20-30 ram Hg.

Benzene, chloroform, methylene chloride, acetone, ether, and

petroleum ether were purified according to standard procedures and

fractionally distilled. Genuine absolute methanol was prepared from

the 99% + product (the usual commercial "absolute" methanol) by treat-

ment with magnesium activated by iodine and distilled before use. Dry

trifluoroacetic acid was prepared from the 99% product (from Aldrich

Chemical Co.) by distilling (without adding any drying agent), and

stored under nitrogen before use.

81

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82

Rate constants were determined by the increase or decrease in

optical density at different appropriate X values depending on the

compounds. The optical density changes by time were monitored on a

Cary-17 ultraviolet spectrometer in samples concentration ranging

-4 from 2.0 to 5.0 X 10 M in various acidic media. Plots of log(A -A)

or log(A-A^) vs. time were linear throughout three or more half-lives,

the rate constants were then obtained by treating data from these

plots according to standard procedures unless otherwise stated. In

general, a small volume (5-2C ul) of stock solution of sample in EtOH

was rapidly added to a previously temperature-equiiibrated cuvette.

The absorbance-time data obtained from these tracings were fitted to

a non-linear least-squares regression anaiysis from which the first-

order rate constant was extracted. The rate constants were deter-

mined based on 3 runs, unless otherwise stated. The standard devia-

tions were calculated by a Texas Instruments SR-51A calculator.

Preparations of 4,4-Dimethylcyclohexa-2,5-Dienone (5a) and 4-Methyl-4-Ethyl-cyclohexa-2,5-Dienone (5b)

The precusors of _5a. and _5b, 4,4-dimethyl- and 4-methyl-4-ethyl-

33 cyclohexenones, were prepared by the methods of Benzing and

Vitullo, and were synthesized by the undergraduate workers in

this laboratory. Thus, 4-methyl-4-ethylcyclohexenone (2.98 g, 22

mmol), DDQ (6.375 g, 1.3 eq), and dioxane (100 ml) were mixed and

refluxed for 60 hr in a 250 ml round-bottom flask. After cooling,

the hydroquinone was filtered off and the dioxane removed at reduced

pressure. The remaining brown oil was chromatographed on a short

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83

neutral alumina column by elution with 10% ether-90% petroleum ether

to yield 2.30 g (77%) of 5h_. The neat infrared spectrum shows bands

at 1615 and 1650 cm (C=C-C=0) . The NMR spectrum shows peaks at

60-75 (3H, t, J=7Hz, CH3 CH^), 1.25 (3H, s, CH3), 1.62 (2H, q, J=7Hz,

CH3 CH^), 6.25 (2H, d, J=10Hz, vinyl), 6.78 (2H, d, J=10Hz, vinyl).

The preparation of _5a, followed the same route as _5b, using isobutyral-

dehyde as the starting material. The NMR spectrum shows peaks at

61.28 (6H, s, CH ), 6.15 (2H, d, J=10Hz, vinyl), 6.87 (2H, d, J=10Hz,

vinyl).

Preparation of 4-Methyl-4-Carbethoxy-cyclohexa-2,5-Dienone (5c)

This compound was prepared by the procedure described previously.

The infrared spectrum (film) shows bands at 1740, 1670, 1640, 1615 cm .

The NMR spectrum (CCl^) shows peaks at 61.28(3H, t, J=7Hz, ester Me),

1.50(3H, s, C-4 Me), 4.23(2H, q, J=7Hz, ester CH^), 6.32(2H, d, J=

lOHz, vinyl), 7.06(2H, d, J=10Hz, vinyl).

Preparation of 4-Methyl-4-Methoxycyclo- ^ ^ hexa-2,5-Dienone(7a) ^.:^^^.,_-^ ^ _.:

^ -.. ^ /.

A solution of thaliium (III) nitrate (TTN) (0.5 g) in dry iethanol

(250 ml) as added to â^stirred; cooled (0 C) solution of the p-cresol

(2.6 g, 24 mmol) in methanol (50 ral)' and'the mixture allowed to warm

to the room temperature (approximately 3 hr). Petroleum ether (200

ml) was then added, the thallium (I) nitrate which precipated was

removed by filtration, and the filtrate was passed down a short

column of basic alumina using petroleura ether as eluent. Evaporation

of the elute gave the crude product. Due to the presence of a yellow

Page 91: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

84

color, a second column chromatograph was necessary to remove this color.

Crystallization from methanol gave the pure compound a, m.p. 60-61°C.

The yield is low (less than 25%). The NMR spectrum (CDCI3) shows

peaks at 61.45(3H, s, CH3), 3.25(3H, s, OCH3), 6.32(2H, d, J=10Hz,

vinyl), 6.78(2H, d, J=10Hz, vinyl).

Preparation of 4-Ethyl-4-Methoxycyclo-hexa-2,5-Dienone (7b)

The procedure was the same as for ]_a^ above, using g -ethylphenol

as the starting material. Crystallization from petroleum ether gave

crystalline Tb , ra.p. 62-65°C. The NMR spectrura shows peaks at 60.83(3H,

t, J=7Hz, CH3 CH^), 1.73(2H, q, J=7Hz, CH^CH^), 3.25(3H, s, OCH3),

6.35(2H, d, J=10Hz, vinyl), 6.77(2H, d, J=10Hz, vinyl).

Preparation of 4-Methyl-4-Carbethoxycyclo-hexa-2,5-Dienone (7c)

c

(A) Preparation of Ethyl Methoxyacetate

Ethyl chloroacetate (613 g, 5 raol) was added dropwise to 1 liter

of 5.0 M NaOCH- solution at 0 C and the reaction mixture was stirred

ovemight at room temperature. After the methanol was distilled

away, the NMR spectrum showed in addition to the expected peaks, a

singlet peak at 63.70, due to methoxyacetate by-product. Thus, 500 ml

of absolute ethanol was added with a few drops of H_SO, and the

mixture refluxed overnight. After the solvents (methanol and

ethanol) were removed, this transesterification reaction was repeated

again for an additional 24 hr (with 500 ml of fresh ethanol) to ob-

tain 254 g (2.15 mol, 43%) of etheyl raethoxyacetate b.p. 125-130°C.

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85

(B) Formylation of Ethyl Methoxyacetate

A mixture of 136 g (1.15 mol) of ethyl methoxyacetate and 128 g

(1.5 eq) of ethyl formate was added dropwise to a large three-necked

flask containing 26.5 g (1.0 eq) of granulated sodium suspended in

500 ml of dry ether in an ice bath. The raixture was stirred for 1

day, and a brown precipitate formed as the sodium disappeared. The

sodium salt was dissolved in 500 ml of water, and the Ph of the

aqueous layer was adjusted to about 8 with 5% HCl, and the ether layer

was removed.

(C) Reaction of Formyl Ester with Methyl Vinyl Ketone

Without any further purification, 80.6 g (excess) of methyl vinyi

ketone (MVK) was added to this slightly basic aqueous solution and

then stirred 24 hr at 0 C. The organic layer was taken up by ether,

solvent removed, and distilled under reduced pressure (0.25 mm, 95-

99°C) to collect 56.5 g (23% frora ethyl methoxyacetate) ethyl 2-formyl-

2-methoxy-5-oxocaprate (13). The NMR spectrum shows peaks at 61.33

(3H, t, J-7HZ, CO^CH^CH^), 2.i5(3H, s, COCH3), 2.30-2.60(4H, mult,

methylene), 3.40(3H, s, CH3), 4.30(2H, q, J=7Hz, CO^CH^CH^), 9.67 (IH,

s, aldehyde).

(D) Cyclization of Ethyl 2-Formyl-2-Methoxy-5-Oxocaprate

Ethyi 2-formyl-2-methoxy-5-oxocaprate (43.76 g, 200 mmol), piperi-

dine (5 ml), acetic acid (5 ml), and benzene (150 ml) were refluxed

into a Dean-Stark trap for 24 hr. Removai of benzene, dissolving the

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86

residue in ether and washing twice with water, drying, and removal of

the ether and followed by distillation through a short Vigreux

column gave 10.77 g (54.5 mmol, 27%) of 4-methoxy-4-carbethoxycyclo-

hex-2-enone (15) , b.p. 100-105°C (0.4 mm) . The NMR spectrum shows

peaks at Ô1.17(3H, t, J=7Hz), 2.1-2.8(4H, m), 3.4(1H, s), 4.25(2H, q,

J=7Hz), 6.05(2H, d, J=10Hz, vinyl), 6.97(2H, d, J=10Hz, vinyl).

(E) Oxidation of 4-Methoxy-4-Carbethoxycyclo-hex-2-Enone

2-methoxy-4-carbethoxycyclohex-2-enone (3.44 g, 7a7 mmol), t-BuOH

(150 ml), glacial HOAc (2.6 ml), and SeO^ (2.25 g, 1.0 eq) were re-

fluxed for 20 hr. An additional 1 g of SeO^ was added and the black

mixture refluxed an additional 20 hr. The mixture was filtered and

worked up by the method of Wettstein. Thus, the brown filtrate was

concentrated in vacuo, taken up in EtOAc, washed successively with

minimum volumes of dilute NaHCO^, water, cold dilute (NH^)_S, cold

dilute NH,OH, water, and then dried over MgSO^. Evaporation of the

solvent gave 0.95 g of crude yellow oil which was chromatographed

over silica gel (with 5% ether-petroleum ether) and crystallized

from ether-petrolum ether to collect 600 rag of white crystals m.p.

60-62°C. The NMR spectrum shows peaks at ôl.25(3H, t, J=7Hz, CO^CH^-

CH3), 3.30(3H, s, OCH3), 4.20(2H, q, J^^Hz^CO^CH^CH^), 6.42(2H, d,

J=10Hz, vinyl), 6.84(2H, d, J=10Hz, vinyl). Anal. Calcd. for C^QH^^*^^

C, 61.22; H, 6.16. Found: C, 61.01; H, 6.22.

•Preparat ion of 4 ,4-Dimethylcyclohexadienol (8a) and 4-Methyl-4-Ethylcyclohexadienol (8b)

4,4-Dimethylcyclohexadienone (5a) (246 mg, 2.0 mmol), LiAlH^ (75

Page 94: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

87

mg, excess), and dry ether (10 ml) were stirred in a closed 25 ml

round-bottom flask at 0 C. Small ice chips were added after 25 min.

Then an excess amount of Na^SO, was added, filtration and solvent

removal furnished 248 mg (99%) of a. The NMR spectrum shows peaks

at Ô1.02(3H, s, CH3), 1.08(3H, s, CH3), 2.63(1H, broad s, OH), 4.32

(IH, s, CHOH), 5.63(4H, s, vinyl). The infrared spectrum (film) shows

bands at 3100-3500 (OH) and 3020 cm"" (C=C) .

Preparation of 21 followed the procedure for E, using _5b as

starting material. The yield was 99%. The NMR spectrum shows a ca.

1:1 raixture of two isomers, and shows peaks at 60-69 and 0.74(3H total,

two triplets, J=7Hz, CH CH ), 1.02 and 1.08(3H total, two singlets,

CH ) , 1.35 and 1.38(2H total, two quartets, J=7Hz, CH^CH^), 2.5(1H,

broad s, OH) , 4.45(1H, broad, CHOH), 5.53(2H, d, J-lOHz, C-3 and C-5) ,

5.85(2H, double doublets, J=10Hz and 3Hz, C-2 and C-6) .

Preparation of 4-Methyl-4-Carbethoxycyclo-hex-2,5-Dienol (8c)

4-Methyl-4-carbethoxycyclohex-2,5-dienone (5c) (405 mg, 2.07 mmol)

and 1 ml of dry THF were mixed in a 25 ml three-necked flask which

was fitted with a serum cap, stirring bar, and a condenser connected

to a mineral oil bubbler, and the reaction mixture was cooled to 0 C

with an ince bath. Then 5 ml (2.50 mmol) of a 0.5 M 9-Borabicycio 3,3,1

nonane (9-BBN) in THF was added dropwise with a syringe over a period

of 5 min. After the system was stirred at room temperature for 3

hr, 2 ml of methanol was added to destroy excess 9-BBN. Then 50 ml

of water was added and the mixture was thoroughly extracted with

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88

methylene chloride. The organic phase was dried over MgSO, and the

volatiles were in vacuo- The residue was chromatographed

7 3 . on a / X -g m . column of silica gel using 15% ether-petroleum ether

to yield 312 mg (76%) of 8£. The NMR spectrum shows a £a. 1:1 mix-

ture of two isomers, and shows peaks at 61.30(3H total, t, J=7Hz,

ester Me), 1.35 and 1.42(3H total, two singlets, Me Me), 2.40(1H, s,

OH), 4.15(2H total, q, J=7Hz, CO^CH^CH^), 4.5(oH, broad d, CHOH), 5.93

and 6.00(4H total, two singlets, vinyl).

Preparations of 4-Methyl-4-Methoxy-and 4-Ethyl-4-Methoxycyclohex-2,5-Dienols (9a and 9b)

Compounds a and 21 were prepared following the procedures for a

and 21» using ]a^ and Th^ as starting materials, respectively. The

yields of these two products are low (50-60%), presumably due to the

loss in the work-up procedures, since these compounds are fairly

volatile and water soluble. The NMR spectrum of a shows £a.. 1:1

mixture of two isomers, and shows peaks at 61.30 and 1.35(3H total,

two singlets, CH^), 2.55(1H, broad s, OH), 3.05 and 3.18(3H total,

two singlets, OCH3), 4.50(1H, mult, CHOH), 5.62 and 5.8(2H total,

d, J=9Hz, vinyl), 5.95-6.30(2H total, mult, vinyl). The NMR spectrum

of 21 shows £a. 1:1 mixture of two isomers, and shows peaks at 60.75

and 0.80(3H total, two triplets, J=7Hz, CH CH3), 1.60 and 1.64(2H

total, two quartets, J=7Hz, CH^CH^), 2.85(1H, broad s, OH), 3.08 and

3.18(3H total, two singlets, OCH3), 4,50(1H, mult, CHOH), 5.60 and

5.63(2H total, two doublets, J=10Hz, vinyl), 6.05-6.35(2H total, mult,

vinyl).

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89

Preparation of 4-Methoxv-4-Carbethoxy-cyclohex-2,5-Dienol (9c)

The procedure for preparing 9£ was the same as described for 2£,

using _7£ as the starting material. The yield was 72%. The NMR

spectrum shows a £a.. 1:1 mixture of two isomers, and shows peaks at

61.28 and 1.32(3H total, two triplets, J=7Hz, ester Me), 2.78(1H,

broad s, Oh), 3.20 and 3.28(3H total, two singlets, OCH3), 4.21 and

4.24(2H total, two quarters, J=7Hz, CO^CH^CH^), 4.50(1H, broad s,

CHOH), 5.70-6.05(2H total, mult, vinyl), 6.10-6.55(2H total, mult,

vinyl).

The rearrangements of _5a,, _52, and 5£ were carried out in CF/,COOH

and in varying concentrations of aqueous sulfuric acid, and the re-

suits will be discussed below.

Rearrangement of 4,4-Dimethylcyclo-hexa-2,5-Dienone (5a)

(A) In CF3COOH

The rearrangement product is 3,4-dimethylphenol, according to

previous work. The rearrangement was determined by monitoring the

increase in UV absorption at \ 276 nm due to the formation of this pro-

duct, and k ,_ thus obtained was 6.82 + 0.10 x 10 sec at 25 C, obs —

and 4.92 + 0.15 x 10~ sec~ at 45°C.

(B) In Aqueous H«SO,

The rearrangement product is 3,4-dimethylphenol, as reported. *

The rearrangement was determined by monitoring the increase in UV

Page 97: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

90

absorption at X 276 nm due to the formation of these products, and the

\bs ^^^^ obtained was 1.35 + 0.05 x 10~^ sec~^ in 60% (by weight)

aqueous H^SO, at 25°C.

Rearrangement of 4->fethvl-4-Ethyl-cyclohexa-2,5-Dienone (5b)

(A) in CF3COOH

The rearrangement products are 3-ethyl-4-methylphenol (major, >98%)

and 3-methyl-4-ethylphenol (minor, >2%). ^ The rearrangement was

determined by monitoring the increase in UV absorption at A 276 nm due

to the formation of these products, and the k , thus obtained was obs

3.57 + 0.12 X 10" sec~- at 25°C, and 2.46 + 0.08 x lO"- sec"" at 45°C.

(B) In Aqueous H^SO,

The rearrangement products are 3-ethyl-4-methylphenol (major,

98%) and 3-methyl-4-ethylphenol (rainor, 2%), as determined by monitor-

ing the increase in UV absorption at X 276 nra due to the formation of

-4 -1 these products, and k , thus obtained was 1.05 + 0.03 x 10 sec in

obs —

52% (by weight) H SO, (aq) , and 3.41 + 0.10 x 10~^ sec~''" in 60% (by

weight) H^SO, (Aq) solutions at 25°C.

Rearrangement of 4-Methyl-4-Carbethoxy-cyclohexa-2,5-Dienone (5c)

(a) In CF3COOH

The rearrangement product is 4-methyl-3-carbethoxy-phenol (X

max 255 nm). Because the cutoff value for CF3COOH is ££. 255, the re-

arrangement of _5£ was determined by monitoring the increase in UV

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91

absorption at X 267 nm due to the formation of product, and k , thus obs

obtained was 9.04 + 0.04 x 10~^ sec"" at 25°C, and 6.17 + 0.10 x 10~^

sec~ at 45°C.

(B) In Aqueous H^SO,

There are two reactions occuring for _5£ in aqueous H^SO,: one

is rearrangement which leads to 3-carbethoxy-4-methylphenol, the other

is decarboxylation which leads to -methylphenol. The relative rate for

each reaction varies with the concentration of the sulfuric acid solu-

tion. The more concentrated the sulfuric acid solution, the less de-

carboxylation occurred.

The total rate constant of rearrangement and decarboxylation

was determined by monitoring the decrease in UV absorption at 260 nm

due to the disappearance of 5c, and k , thus obtained were 9.82 + 0.20

— obs — -5 -1 -4 -1

X 10 sec in 52.0% H^SO^, 4.16 + 0.09 x 10 sec in 60.8% H^SO^, -3 -1

and 1.18 + 0.05 x 10 sec in 70.4% H^SO, . The percentages of

rearrangement product in the product mixture were estimated by NMR

spectroscopy. In general, approximately 150 mg of _5£ was added to

50 ml of aqueous H^SO, solution and stirred at 25 to the reaction is

over. Then water (150 ml) was added, extracted with CH Cl_, solvent

removal to afford a mixture of rearrangement product (20) and £-

Cresol. The yields in all three solutions were bigger than 85%

theoretical values. The NMR spectra show 21%, 41%, and 64% compound

20 in the product mixture in 52.0%, 60.8%, and 70.4% H^SO^, respec-

tively.

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92

Protonations of Dienone (5a), (5b). and (5c) in CF^fOOH

The degrees of protonations of series 2 in CF3COOH were estimated

by NMR spectroscopy. Thus, to £a. 20 mg of dienones 2 in an NMR

tube (with TMS) was added a suitable amount of CF3COOH and scanned

immediately to obtain the chemical shift values of the vinyl protons.

After discarding half of the solution in this tube, a fresh portion

of CF3COOH was rapidly added and the spectrum was scanned again.

This procedure was repeated several (at least 4) times. The chemical

shift values for the vinyl protons were constant in the more dilute

solutions. Comparing these values tc the chemical shifts (in CDCl.,)

of the same dienone, the chemical shift differences induced by the

protonation were obtained: a = 0.36, 6 = 0.51 p.p.m. for _5£. Thus,

it was calculated 57% protonation for 5a., 57% for _52, and 39% for _5£,

respectively.

Rearrangement of 4-Methoxy-4-Methylcyclo-hexa-2,5-Dienone (7a)

The rearrangements of methoxy dienone series ]_ were carried out

in 1:1 ratio of CF3COOH/CH3COOH solution, and 60% (by weight) aqueous

H/,SO, solution at 25 C. The results are discussed below. 2 4

(A) In 1:1 ratio of CF3COOH/CH3COOH

The rearrangement product was identified as 3-methyl-4-methoxy-

phenol by NMR spectroscopy and by comparing its methyl ether with an

48 authentic sample. The rearrangement of ]a^ was determined by monitor-

ing the increase of UV absorption at X 277 nm due to the formation

of this product. Due to the fact that the rearrangement product can

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93

undergo a very slow dimerization reaction in contact with air in this

acidic medium, the solvent was flushed with N^ and the cuvette was

tightly stoppered to minimize contact with oxygen. The half life for

the rearrangement of 7a_ was weeks in this medium, so a Guggenheim

plot was used to determine the rate constant, and k , thus obtained obs

was 5.55 + 0.25 X 10~^ sec""'-, based on 2 runs.

(B) In 60.8% H,,SO, 2 4

The rearrangement product was identified to be the same as in

CF3COOH/CH3COOH media by NMR and UV spectroscopy. The product can

undergo a slow diraerization reaction after the rearrangeraent is over.

The k , in this medium was 1.27 + 0.02 x lO"^ sec"''' at 25°C. obs —

Protonation of fethoxy Dienones (7a, 7b, and 7c) in 1:1 Ratio of CF/,COOH/CH.,COOH J J

Methoxy dienone _7a. was treated in the same fashion as described

in series 2 i^ an NMR tube to obtain the vinyl protons' chemical shift

differences between the unprotonated and protonated ]a_ in 1:1 ratio

of CF^COOH/CH^COOH:^ = 0.24, 6 = 0.42. Because the adjacent -OCH3

group could influence the chemical shift difference value of 3 hydrogen,

a hydrogen's value was used for this calculation. Assuming the chemical

shift difference of a hydrogen for ]_ is the same as 2 between the un-

protonated and fully protonated forras, it was estimated £a_. 27% pro-

tonation for ]a^, Because dienone _7£ rearranges too fast to measure

the protonation behavior by the dilution method, a different way was

used. Thus, four different dilute concentrations of 2£ ii 1-1 ratio

of CF3COOH/CH3COOH (with TMS) were prepared and scanned immediately to

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94

obtain four sets of the chemical shift vaiues of vinyl protons. It

was assumed that the most dilute acidic solution approxiamtes the con-

centration in the UV cuvette and thus the protonation behavior is the

same as well. The calculated chemical shift differences between the

unprotonated and protonated 7£ in this acidic medium were: a = 0.19,

6 = 0.35. It was estimated £a. 21% protonation for ]_c^.

Rearrangement of 4,4-Dimethylcvclo-hexadienol (8a)

The rearrangements of all three 4-methyl-4-R-cyclohexadienols

(8a, 21» and 2£) were carried out in four sets of buffer solutions

(y = 0.1, NaCl) which consisted of 60:40 (by volume) aqueous HCl and

EtOH, and the pH values were (A) 1.83, (B) 2.03, (C) 2.11, (D) 2.34,

respectively, as measured by a Beckman Altex <î> 71 pH meter.

Monitoring the rearrangement of each compound at X 259 nm shows

evidence of biphasic reaction, i.e., the absorbance increases due to

the formation of the conguhated isomer (8a', 8b', and 8c') followed

by a decrease in OD due to the formation of the rearranged product.

The isomerization and rearrangement in each case were treated as

separabie consecutive first-order reactions, and were monitored at

X 259 nm for all three compounds (8a, 8b, 8c) at 25 C. The rate

constants of these isomerizations were obtained by the Guggenheim

method, and the first few points of the OD data of the rearrangements

were discarded to avoid the deviation caused by the isomerization

reaction. In each case, the Guggenheim plot of the isomerization and

the plot of log(A-A^) vs_. time of the rearrangement were linear except

for a rare stray point.

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95

The rearrangement product of 8a. was shown to be £-xylene. -

^obs °^ ^^^ isomerization is 2.70 + 0.10 x 10~^ sec~- in solution (D) ,

and was too fast to follow in the stronger acid solutions. K for obs

the rearrangements in solutions (a), (B), (C), (D) were 2.90 + 0.08

X 10~ , 2.02 + 0.10 X 10~- , 1.20 + 0.08 x lO"^, and 9.08 + 0.25 x 10~^

o at 25 C, respectively.

Rearrangement of 4-Methyl-4-Ethvl-cyclohexadienol (8b)

The rearrangement product of 21 was shown to be £-ethyltoluene

by UV (X 275 nm) and NMR analysis. K , for the isomerization max •' obs

was 1.01 X 10 sec in solution (D); for the rearrangements in

solutions (A), (B), (C), and (D) were 3.46 + 0.14 x 10~^, 2.38 + 0.10 0 O 0 1

X 10 , 1.40 + 0.05 X 10" , 1.01 + 0.35 x lO" sec~ at 25°C, respec-

tively.

Rearrangement of 4-Methyl-4-Carbethoxy-cyclohexadienol (8c)

The rearrangement product of 2£ was shown to be £-carbethoxy-

toluene from the UV spectrum (X 275 and 284 nm). K , of the ^ max obs

-4 -1 isomerization is 1.34 + 0.08 x 10 sec in soltuion (D); for the

—6 rearrangements in solutions (A), (B), (C) were 9.0 + 0.02 x 10 ,

6.30 + 0.12 X 10~^, 3.70 + 0-10 x 10~ sec~ at 25°C, respectively.

The isomerization product of 2£» 6-methyl-6-carbethoxycyclohexa-

2,4-dienol (8c'), has a X at 256 nm, e 1650. From the spectral max

parameter published for 5,5-dimethyl-l,3-cyclohexadiene (X^^^ =

257 nm, e 43000), used as a model for the chromophore, the equili-' max

veium constant for 8c'/8c is 0.65 in solution (A), and presumably

Page 103: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

96

essentially the same in the other acidic solutions (B) , (C), and (D) .

Reactions of 4-Methoxv-4-R-Cyclohexa-dienols (9)

Monitoring 4-methoxy-4-methyl- and 4-methoxy-4-ethylcyclohexa-

dienol (a and 21) in buffer solutions (A) and (C) gave very similar

rate constants, i.e., 3.54 + 0.10 and 1.52 + 0.05 x 10~^ sec """ for 9a;

2.94 + 0.11 and 1.24 + 0.05 x lO"^ sec""'" for 21» and the products

from these two reactions show very similar UV spectra (X = 275 and max

284 nm for a; 275 and 283 nm for 21) •

Further investigation showed that, instead of rearrangeraent,

these two compounds undergo decomposition reactions. Thus, 21 (^ °§»

with appropriate amount of CDCl^) in an NMR tube was added a few drops

of CFoCOOH. Compound 22 ^^ converted in seconds to a new compound

which identified as _£-ethylphenol. The reaction of 21 ^^ weak acidic

solution (A) shows the same product. Reaction of 2£ with CF3COOH

gave _2 -methylphenol according to NMR spectroscopy. Instead of rearrange-

ment, 2£ also undergoes decomposition in buffer solution (E) (Ph =

1.27 aqueous HCl, u = 0.1, NaCl) and CF3COOH to a new species 0 ^ ^ =

255 nm) which by NMR and UV analysis was shown to be _g -carbethoxy-

phenol in solution (E), and £-carbethoxyphenyltrifluoroacetic ester in CF_COOH. In CF3COOH, the conversion is complete within 1 min;

—6 —1 in solution (E), the k is estimated to be ca. 10 sec by UV

obs observation.

Rearrangement of l,l-Diphenvl-2-Methyl-1.2-Propanediol (lOa)

The rearrangement of the pinacols (lOa, lOb, and lOc) were

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97

carried out in 1:1 ratio of CF3COOH/CH3COOH and solution (F) (H SO, -

HOAc - H^O, 45.0:17.0:38.0) at 25°C. The results are discussed below.

The rearrangement products in these two acidic media were 3,3-

diphenyl-2-butanone (major) and a-phenylisobutyrophenone (minor)

according to the NMR spectroscopy and previous work by Schubert.

The rearrangement of lOa was determined by monitoring the increase

in UV adsorption at X 290 nm due to the formation of products.

(A) In 1:1 Ratio of CF3COOH/CH3COOH

The kinetic study shows that the rearrangement was not following

a pseudo-first-order kinetics, i.e,, the log(A -A) y£. tirae plot

exhibits a break with an overail concave upward shape. The k

-3 -1 values were 3.98 + 0.17 x 10 sec for the first part of the reac-

-4 -1 o tion, and 1.90 + 0.04 x 10 sec for the second at 25 C. The phenyl

vs. methyl migration ratio was determined by the method of Schubert,

and was 0.22 + 0.01.

(B) In Solution (F)

The reaction now follows the pseuod-first-order kinetics, and

k is 7.66 + 0.20 X lO"" sec" at 25°C. The phenyl v£. methyl obs —

migration ration was 0.135 jf 0.005.

Rearrangement of l,l-Diphenvl-2-Methyl-1,2-Butanediol (lOb)

The rearrangement products of Ob were 3,3-diphenyl-2-pentanone

(22» ethyl migration product), l,2-diphenyl-2-methylbutanone (22»

phenyl migration product), and 4,4-diphenyl-3-pentanone (22» methyl

migration product). The rearrangement was determined by monitoring

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98

the increase in UV absorption at 290 nm due to the formation of the

products, and was followed the first-order kinetics. The k values obs

—2 —1 thus obtained were 1.47 + 0.05 x 10 sec in 1:1 ratio of CF^COOH/-

CH3COOH, and 1.96 + 0.04 x 10~^ sec -'" in solution (F) at 25°C.

Product analysis was carried out by NMR spectroscopy. Thus, 110

mg of lOb was added to a solution (20 ml) of 1:1 ratio of CF3COOH/-

CH3COOH and allowed to stir for 6 hr at room temperature, then ex-

tracted with dilute NaHCO,, , . and CH,.C1,, several times to remove the 3(ag) 2 2

acids. The organic phase was combined, dried, solvent removed to give

a mixture of products. The XL-IOO NMR spectrura of this raixture showed

mostly ethyl migration product (28) (see Fig. 2, page 57). In order

to sort out the ratio of these products, NMR shift reagent, Resolve-

Al EuFOD , was introduced gradually to afford Fig. 3 (see page 58).

The ratio of products was determined by integrating the methyl peaks

of each product, and found 95% ethyl, £a.. 4% phenyl, and £a. 1%

methyl migration products. The product analysis of lOb in solution

(F) was carried out in the same fashion as above, and was found 93%

ethyl, 5% phenyl, and £a. 2% methyl raigration products (see Fig. 4,

page 62).

Rearrangement of l,l-Diphenvl-2-Carbethoxy-1,2-Propenediol (lOc)

The rearrangement product of 10£ in 1:1 ratio of CF3COOH/CH3COOH

was l,l-diphenyl-l-carbethoxy-2-propanone according to NMR spectro-

scopy. The rearrangement was determined by monitoring the increase

of UV absorption at X 263 nmr due to the formation of the product, and

k thus obtained was 4.84 + 0.16 x 10~^ sec"^ at 25°C. This compound obs

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99

undergoes slow decarboxylation in solution (F). Therefore, no measure-

ment of the rearrangement rate was possible.

Rearrangement of Epoxides 34a, 34b, and 34c

The rearrangements of epoxides _34_ were carried out in 1:1 ratio

of CF3COOH/CH3COOH at 25°. Compound 34a has a very fast rate for

approximately the first half of the reaction, followed by a much

slower rate when monitoring the formation of the product 36a at 290

nm. The first part of the rearrangement was too fast to follow by UV

spectroscopy. However, the second part's rate constant is 1.86 + 0.04

X 10 sec

Compound 3^ rearranges so fast that the reaction is complete

in secondsa Thus k-, is estimated to be >10 sec . Ibs

Compound V^ was monitoring the product (36c) formation at 263

obs

-3 -1 and 285 nm, and k thus obtained was- 4.62 + 0.21 x 10 sec .

Page 107: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

LIST OF REFERENCES

^' ^^^ f-;/; n° f ' ^"^ ^' °^^^°' ^^- "Molecular Rearrangements, Part I, Interscience, 1963, pp. 1-25-(b) D. Bethell and V. Gold, "Carbonium lons, and Introduction,"

Academic Press, New York, 1967, pp. 204-211.

2. H. 0. House, J. Am. Chem. Soc., 22, 1235 (1954).

3. H. 0. House and D. J. Reif, J. Am. Chem. Soc, 77, 6525 (1955).

4. H. 0. House, J. Am. Chem. Soc, 22» 2298 (1956).

5. H. 0. House and R. L. Wasson, J. Am. Chem. Soc , ]9_, 1488 (1957).

^' 2490* ( °'' ' * * ^^^^* ''' * * ^^^^°''' - ^- ^ " - S°^-' Zl'

7. H. 0. House and D. J. REif, J. Am. Chem. Soc, _79, 6491 (1957).

8. H. 0. House and G. D. Ryerson, J. Am. Chera. Soc , _82, 979 (1961).

9. H. Plieninger and T. Suehiro, Ber., 2798 (1956).

10. S. Inayama and M. Yanagita, J. Org. Chera., 2Z.» ^^65 (1962).

11. R. H. Churi and C. E. Griff n, J. Am. Chera. Soc, 22» ^824 (1966).

12. M. Sprecher and D. Kost, Tetrahedron Letters, No. 9, 703 (1969).

13. Y. Pocker, Chem. Ind. (London) 332 (1959).

14. M. Yanagita, S. Inayama, M. Hirakura and F. Seki, J. Org. Chem. , 22» 690 (1958).

15. N. L. Wendler, in P. de îfeyo (Ed.), M lecular Rearrangements, Part 2, Interscience Publishers, New York, 1028 (1964).

16. R. B. Woodward and T. Singh, J. Am. Chem. Soc , 22» ^^^ (1950).

17. J. N. >ferx, J. Craig Argyle, and Lewis R. Norman, J. Am. Chem. Soc, 26, 2121 (1974).

18. (a) V. P. Vitullo and N. Grossman, Tetrahedron Letters, 559 (1970); (b) V. P. Vitullo, Chem. Commun., 688 (1970); (c) V. P. Vitullo and N. Grossman, J. Am. Chem. Soc, 2^, 3844

(1972).

19. J. N. Marx and E. J. Bombach, Tetrahedron Letters, 2391 (1977).

100

Page 108: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

101

20. For a summary and leading references, see: P. Brownbridge, Pa Ka

oo-^^f^^"''' ^' ^^^P ^'''^ ^' W^^^en, J. Chem. Soc, Perkin I, 2024 (1976).

21. (a) E. C. Friedrich, J. Org. Chem. , 22» ^ 13 (1968); (b) V. P. Vitullo, J. Org. Chem., 21» 224 (1969); (c) K. L. Cook, M. J. Hughes, and A. J. Waring, J. Chem. Soc,

Perkin Trans. II, 1506 (1972).

22. M. S. Newmann, D. Pawelek, and S. Ramachandran, J. Am. Chem. Soc, 21» 995 (1962).

23. V. Pa Vitullo, M. J. Cashen, J. N. Marx, L. J. Caudle, and J. R. Fritz, J. Am. Chem. Soc, OO, 1205 (1978).

24. M. Stiles and R. P. >feyer, J. Am. Chem. Soc , 21» 1 97 (1959).

25. P. D. Bartlett and Thomas T. Tidwell, J. Am Chem. Soc, 90, 4421 (1968). —

26. (a) M. J. Hughes and A. J. Waring, J. Chem. Soc, Perkin II, 1043 (1974);

(b) J. W. Pilkington and A. J. Waring, ibid., 1349 (1976).

27. (a) J. N. Marx, Tetrahedron Letters, 4957 (1971); (b) N. C. Deno, H. G. Richey, N. Friedraan, J. D. Hodge, J. J.

House, and C. 0. Pittman, J. Am. Chem. Soc, 22» 2991 (1963); (c) R. J. Zalewski and G. E. Dunn, Can. J. Chem. , _42, 2264 (1969); (d) G. A. Olah, Y. Halpern, Y. K. Mo. and G. Liang, J. Am. Chem.

Soc, 21» 3554 (1970); (e) V. P. Vitullo, J. Org. Chem., 21» 224 (1969).

28a J. E. Dubois and P. Bauer, J. Am. Chem. Soc, 2 » ^^IO (1968).

29. Ra L. Heidke and W. H. Saunders, Jr., ibid •» 21» ^^^6 (1966).

30. T. Yvernaut and M. >fezel, Bull Soc Chim. Fr., 638 (1969).

31. H. C. Brown, "The Nonclassical lon Problem," Plenum Press, New York, N. Y., (1977) .

32. A number of undergraduate students prepared these samples.

33. E. Benzing, Angew. Chem., 2i» 521 (1959).

34. V. P. Vitullo, J. Org. Chem., 21» 3976 (1970).

35. John N. >ferx and Lewis R. Norman, Tetrahedron Letters, 2867 (1973)

Page 109: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

102

36,

37.

38.

39,

40.

(a) H. Plieninger, G. Ege, H. J. Grasshoff, G. Keilich, and W. Hoffman, Ber., 21, 2115 (1961).

^ ^ l' ^}^^^^''^^ll ^ ^^^°1^' R- Fisher, and W. Hoffman, ibid., 21, 1774, 1765 (1965).

^10^^"^"^"^°^* °* "• ^^'"''y* ^""^ M. Edwards, J. Org. Chem., 41, 283 (197 6).

This compound was prepared by Danny Peckenpaugh, John Mbntgomery, and Reza Fathi in this lab.

Jean-Louis Luche, J. Am. Chem. Soc, OO, 2226 (1978).

S. Krishnamurthy and H. C. Brown, J. Org. Chem., _40, 1864 (1975).

41. S. Danishefsky, K Hirama, N. Fritsch, and John Clardy, J. Am. Chem. Soc, 101, 7013 (1979).

42. These compounds were prepared by Rickey Gross, Russ Hill, Terry Thames, and Bennie M:Williams in this lab.

43. C. L. Stevens and C. T. Lenk, J. Org. Chem., 22, 538 (1959).

44. Rickey Gross, Russ Hill, and some minor contribution from a number of undergraduate students in this lab.

45. H. H. Hyman and R. A. Garber, J. Am. Chem. Soc, 21» 1847 (1959).

46. Robert W. Taft, Elton Price, Irwin R. Fox, Irwin C. Lewis, K. K. Andersen, and George T. Davis, ibid., 85, 709 (1963).

47. V. P. Vitullo, J. Org. Chem., 21» 224 (1969).

48. This experiment was carried out by Elizabeth Hall and Patsy Woods in this lab.

49. This dimer was synthesized by Nim Batchelor in this lab.

50. C. W. Spangler and P. L. Boles, J. Org. Chem., 3]_, 1070 (1972).

51. W. M. Schubert and Paul H. LeFebre, J. Am. Chem. Soc, 2Í» 1639 (1972).

52. (a) K. L. Cook and A. J. Waring, J. Chem. Soc, Perkin II, 84 (1972).

(b) K. L. Cook and A. J. Waring, ibid., 88 (1972).

53. E. A. Guggenheim, Philos, >feg., 2» ^^^ (1926).

54. G. S. Hammond, J. Am. Chem. Soc., 77, 334 (1955).

Page 110: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

103

55. P. D. Bartlett, Nonclassical lons, Benjamin, New York (1965).

56. W. J. le Noble, Highlights of Organic Chemistry, M. Dekker, New York (1974).

57. P. G. Gassman and A. F. Fentiman, Jr., J. Am. Chem. Soc, 92, 2549 (1970).

58. H, C. Brown, M. Ravindranathan, and C. G. Rao, J. Am. Chem. Soc , 100, 1218 (1978)a

59. S. Danishefsky, C. F. Yan, and P. M. McCurry, Jr., J. Org. Chem., ^ , 1819 (1977).

60. These corapounds were prepared by Rickey Gross and Benne McWilliams.

Page 111: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

APPENDIX

Guggenheim fethod

104

Page 112: Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

105

k -kt

For a f irst-order reaction, C > D, the equation a - x = ae

holds, where a is the concentration of C, and x is the concentration of

D after time t. Because UV absorption (A) is proportional to the con--kt

centration, this equation can be written as A - A = (A - A^) e , ' ^ oo ^ oo 0

where A^ is the infinite value of the UV absorption, A,. is the value

of the initial absorption, and A is the value of absorption after time

t of this reaction. ^feasurements A-, A_, A^, . . . are absorptions

made at times t , t t/., . . ., and a second series of measureraents

A- , A' A, , . . . are made at times t^ + A, t^ + A, t^ + A, . . .,

where A is a constant increment. For accurate results A should be at

least one and preferably two or three times the half-life of the

reaction. Substituting A^ and Aj into the equation above gives

A - A = (A - A.)e"^^l (1) oo 1 oo 0

A - A: - (A - A-)e ' 1 . . (2) 1 00 U 00

Subtracting (2) from (1) yields

Ai - A, = (A„ - A^)e-'^^1(1 - e--^^

or

-kA In (A| - A^) = -kt^ + In (A^ - A^)(1-e )

= -kt., + constant (3)

Since equations similar to (1) and (2) can be written for t^ and t^ +

A, and so on, the subscript 1 can be dropped, making equation (3)

general for any A and A'.

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