migration tendency of substituents in some cationic rearrangement reactions
TRANSCRIPT
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
••'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
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
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
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
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
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
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
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
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-
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.
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
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
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
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
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
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
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.
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
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
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
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
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
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-
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
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
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
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
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.
CH„ ^ R CH3O. ^R
OH
8
OH
9
a, R = Me; b , R = E t ; c , R = COOEt.
-/~
z '
/
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
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
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
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.
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.
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
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
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
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
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
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
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
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
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
5£
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
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.
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
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
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
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
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.
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
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
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.
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
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
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
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
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
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.
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
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°
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
Xî
<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
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
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
- 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
Pá
4J C cu 00 cO cu >-l +J M-l • H
co
<u x : 4J 5-1 <U 4J <H cO
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
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.
• 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
Oí
• (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
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
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.
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.
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
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
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).
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 .
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
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
1£
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
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.
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
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)
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,
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.
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-
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
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
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
80
electronegative groups which are more stable to acidic media (such
as ketone, cyano, etc.) as substituents in the dienone systems for
further study.
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
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
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
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.
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
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
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
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).
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
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
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.
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
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
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.
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
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
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
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
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 .
LIST OF REFERENCES
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^' 2490* ( °'' ' * * ^^^^* ''' * * ^^^^°''' - ^- ^ " - S°^-' Zl'
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32. A number of undergraduate students prepared these samples.
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36,
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38.
39,
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This compound was prepared by Danny Peckenpaugh, John Mbntgomery, and Reza Fathi in this lab.
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42. These compounds were prepared by Rickey Gross, Russ Hill, Terry Thames, and Bennie M:Williams in this lab.
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103
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APPENDIX
Guggenheim fethod
104
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'.