Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

MIGRATION TENDENCY OF SUBSTITUENTS IN SOME CATIONIC REARRANGEMENT REACTIONS by YEN-LONG VINCENT HONG, B.S.
A DISSERTATION IN CHEMISTRY Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Approved
Accepted
May, 1982
n j ^ - u v '--<-
'V -'l 7 '
^ '
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 direction of this work. Appreciation is expressed to the Welch Foundation for financial support for the experimental work.
11
TABLE OF CONTENTS
ACKNOWLEDGEMENTS LIST OF TABLES LIST OF FIGURES I. INTRODUCTION The Rearrangement of the Electronegative Functional Group The Pinacol-Pinacolone Rearrangement The Dienone-Phenol Rearrangement The Aromatization of Cyclohexadienols The Relative Migratory Aptitude and Migration Tendency. . The Migration Tendency of Et and Me Scope and Purpose of the Present Work II. RESULTS Preparations of the Compounds for These Kinetic Studies . Rearrangements of 4-Methyl-4-R Cyclohexadienones {5)... Rearrangements and Migration Tendencies of 4-Methoxy-4-RCyclohexa-2,5-Dienones (R = Me, Et, COOEt) Ta, ^ , 2 ^ Rearrangements of 4-Methyl-4-R-Cyclohexadienols (r=Me, Et, and COOEt) 8a_, 8b, 8 _ c Reactions of 4-Methoxy Cyclohexadienols (9) Rearrangements of Pinacols (lOa, lOb, and lOc) Suramary III. DISCUSSION General Electronic Factor in Each System iii
ii vi vii 1
2 3 5 12 14 17 22 24 24 32 ^ ^^ 47 52 53 63 65 65 66
Change in Rate-Determining Step for Rearrangement of Pinacols 2P in CF^COOH/CH COOH Transition States for Dienone and Dienol Rearrangement. . Tool of Increasing Electron Demand M!' CH3 Value as a Probe Temperature and Solvent Effects Carbethoxy as a Migration Group IV. V. CONCLUSION EXPERIMENTAL General P r e p a r a t i o n s of 4,4-Dimethylcyclohexa-2,5-Dienone 4 - f e t h y l - 4 - E t h y l c y c l o h e x a - 2 , 5 - D i e n o n e (_5b) P r e p a r a t i o n of Dienone (5c) 4-Methyl-4-Carbethoxycyclohexa-2,583 83 84 84 86 68 72 73 75 77 77 79 81 81 (5a) and 82
Preparation of 4-Methyl-4-Methoxycyclohexa-2,5Dienone ( 7 ) _a Preparation of 4-Ethyl-4-Methoxycyclohexa-2,5Dienone ( 7 ) _b Preparation of 4-Methyl-4-Carbethoxycyclohexa-2,5Dienone (7c) Preparation of 4,4-Dimethylcyclohexadienol (8a) and 4-Methyl-4-Ethylcyclohexadienol (8b) Preparation of 4-Methyl-4-Carbethoxycyclohex-2,5Dienol iSc) Preparations of 4-Methyl-4-Methoxy- and 4-Ethyl-4-Methoxycyclohex-2,5-Dienols (9a and _9b) Preparation of 4-Methoxy-4-Carbethoxycyclohex-2,5Dienol (^) Rearrangement of 4,4-Dimethylcyclohexa-2,5-Dienone (5a) . Rearrangement of 4-Methyl-4-Ethylcyclohexa-2,5Dienone (5b)
IV
87 88
89 89
90
Rearrangement of 4-Methyl-4-Carbethoxycyclohexa-2,5Dienone (5c) Protonations of Dienone ( 5 ) , ( 5 ) , and (^) _a _b Rearrangement of Dienone (7a)
90
in CF^COOH . . 92
4-Methoxy-4-Methylcyclohexa-2,592
Protonation of Methoxy Dienones ( 7 , Th^, and 7^) in 1:1 _a Ratio of CF-,COOH/CH COOH Rearrangement of 4,4-Dimethylcyclohexadienol (8a) Rearrangement of 4-Methyl-4-Ethylcyclohexadienol (8b) . . . Rearrangement of 4-Methyl-4-Carbethoxycyclohexadienol (8c) . Reactions of 4-Methoxy-4-R-Cyclohexadienols (9) 93 94 95 95 96
Rearrangement of l,l-Diphenyl-2-Methyl-l,2-Propanediol (lOa) 96 Rearrangement of l,l-Diphenyl-2-Methyl-l,2-Butanediol (IQb) Rearrangement of l,l-Diphenyl-2-Carbethoxy-l,2-Propanediol (lOc) Rearrangement of Epoxides 34a, 34b, and 34c LIST OF REFERENCES APPENDIX 97
98 99 100 lO'^
LIST OF TABLES
I.
Preliminary Approximate Relative Rate of Compounds _5, 7^, and 10 bv NMR Spectroscopy Rearrangement of 4-Methyl-4-R-Cyclohexadienones ( 5 in _) CF^COOH
21
II.
33 37 39 4L 44 45 49 55 56 61 64
III. IV. V. VI. VII. VIII. IX. X. XI. XII.
Rearrangement of Dienones ( 5 in TFAA/TFA (25) _) Rearrangements of Dienones _ in Aqueous HSO, at 25 . . . . 5 Protonation of Compound 2]^ Rearrangements of Dienones (T^) in CF^COOH/CH^COOH at 25 . . Rearrangements of Dienones "]_ in Aqueous HSO, Rearrangements of Dienols 8 in Acidic Solutions at 25 . . . ^ Rearrangements of Pinacols ( W in CF^COOH/CH^COOH at 25 . Product Ratio of 10 in CF^COOH/CH^COOH Rearrangements of Pinacols (10) in H SO.-HOAc-HÔ at 25. . Summary of Migration Tendencies
VI
LIST OF FIGURES 1. Plot of log (A -A) vs. time for lOa in CF,,C00H/CH.3C00H at
25
2.
. . 7"
"T". . . ? . . . ?
54
57
NMR spectrum (60 MHz) of product mixture of lOb in CF.3COOH/CH^COOH 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 NMR spectrum (100 Miz) of product mixture from rearrangement of lOb in H^SO^-HOAc-HÔ after the NMR shift reagent, Resolve Al EUFODTM^ was added p-a plot of 37 and 38 on 70% aqueous dioxane at 25 C. . . .
3.
58
4.
62 74
5.
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 performed with these compounds. For this reason it is often illustrated
with an example from the terpenes, e.g,,
1 C
^ C+
R^ \ ''+ "- ^ > >.l lC
\ ^ +C
R I C
Isoborneol
camphene
However, it raay be illustrated in sirapler systeras:
CHr 3
CH 1^ C CH^ Cl 1 2 CH3
0H~ HÔÂ
> 7
f3
CH3 C CH CH3 Br
AlBr CH^CH^CH^Br
/
CH^
1 CH
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 transition 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 and esters under a variety of acidic conditions. Ph
\
18
0 -<:H
II c
BF CH, - H3C ^ C 0
Ph
II
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
COOEt COOEt 50% H^SO, 2 4

^
9 hr 0
The third type of rearrangement is theraigrationof the electronegative species to siraple localized carbonium ion centers in open chain compounds. Examples of carbethoxy migration 11 12 * were studied. 0 Ph > - C CH 0 ^H 0 Ph and of phosphorus-
containing species
T PÔC^H^)^
-^TBF^
^P(OC/,H.)/,
2 52
CH,
CHO
Among these studies, the pinacol and dienone-phenol rearrangement are often used as examples. 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 reTherefore, let us first look at these
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, OH
R, R. OH
Scheme I This reaction has been accomplished many times and is a wellknown 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^ 2 R, R/, R, R/,
^ ' ^
R,>CCR/ 2 I I 4 OH OH C = R, ^ R 2
^
OH
^
R, ^4 OH^ +
-H.O
l^ l^
=-^ Ro - C - C - R, ^ "2 H
ir -
R1
CCR,
R/,
s ^,
Ro C
I I
OH
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 aromatization 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 In that case the
with either aqueous sulfuric or hydrochloric acid. product is the phenol.
R.
-H
+
^
2 ^"' ^^
OAc
R, -H+
^
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 pseudodocumenol. 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
-^
AcÔ, H^SO^
-^
CH,
\ ^
CH3 Ô-^
C. H
AcO
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
8 The proposed mechanism is shown in Scheme III:
AcO
OAc
1,2 shift AcO
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 _ ^ in which R=methyl (Me) , ethyl (Et) , isopropyl (i-Pr), ^ 5, benzyl (Bz), and phenyl (Ph). The rearrangements were carried out in trifluoroacetic acid to avoid possible ester hydrolysis. COOEt
0 4
Consideration of the dienone-phenol rearrangement mechanism
18
(Scheme IV) shows that there are three possible rearrangement pathways depending on the substituent R. R COOEt COOEt B
R COOEt
i -1
COOEt. -^ C
' + '
OH A
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 COEt 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 isopropyl. 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,Êt 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 This again gives supportive evidence that path b of
in this case.
Scheme IV is a very high energy pathway and that reactions path c prefer _
11
COOEt
COOEt
COOEt
COOEt
COOE
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
7 bond of the carbonyl group has to back-donate some electron density T 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 T electrons, will not underT 21 22 go such migrations under any conditions. * for carbethoxy group migration was proposed The transition state 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/ R R, + HÔ
^-1 OH
R.
+ H
Scheme V
13 A notable difference between this reaction and the dienonephenol 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 because 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 (8a) has been investigated. 23 This compound shows convenient reMoreover, when â_ is dissolved
arrangement rates in acetate buffers.
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, H+ + (D) H 8a
^
CH.
CH
'3
H
OH
+ H OH H(D) 8a'
+ + H
H(D)
Scheme VI
14 The intermediate (8a') forms -xylene 20 times slower than it is formed through isomerization from ^ . tion and rearrangement of ^ were reported 23 The rates of isomeriza-
in various dilute buffer solutions,
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 Mayer 24 have studied the rearrangements of a series of glycols in The migration of R was studied by
which the R group was varied.
CH/, CH/, " C
R C CHo
I 3 I 3 I
OH
I
OH
a.
R = CH3; b.
R = C^H^; c.
R = ^-C^H
intermolecular comparisons of the rates, using compound ^ as the standard.
(R = CH/j)
Corrections were made, using labeling studies to After the appropriate corrections,
identify the various products.
t h e o r d e r of r e a r r a n g e m e n t of ^ i n 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 cyclohexadienone 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 complicating factors mentioned earlier should be minimized or eliminated. Thus both substituents are held in identical steric environments, so noraigratorypref erence based on stereochemistry can occur. The reac-
tion is induced by protonation on the carbonyl oxygen, so no complication associated with leaving groups can occur. Marx et_. al_. " have studied the rearrangements of compounds _^ ^ 5 where R = Me, COÊt, 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 determined from the same two compounds in aqueous H-SO, appears to reflect a property of the system. 26 and thus
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 Based upon an
charge density is high before the migration occurs.
21c NMR deshielding argument, a calculation that 0.15 of a positive charge unit is at the migration terminus in the protonated cyclohexadienone ion. In contrast, in any system in which there is a
17
CH.
R H
->
0 5
R = Me, COÊt, E t , and Ph l e a v i n g group i n v o l v e d , t h e amount of p o s i t i v e charge b u i l d - u p i s unknown and not d e t e r m i n a b l e , s i n c e t h e m i g r a t i o n can be more or l e s s concerted with d e p a r t u r e of t h e leaving group. The Migration Tendency of Et and Me The m i g r a t i o n tendency of Et v s . Me in t h e dienone system i s much g r e a t e r than in any o t h e r known system. For the p i n a c o l r e 24 For rearrangement
arrangement of j6, i t i s 17, as mentioned above. to a hydroxy-substituted c a t i o n i c center i t i s 2 to 5. 28
in b i s - _ t - a l k y l k e t o n e s ,
h
R/c-C
C-
II
C R^
/1
R,
\ \
H+ slow
R/,-C
C-
R'
I
OH
R
-^
f ast
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'
CHÔH
R'
^CHÔH
CHÔH
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 rearrangement 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 theraigrationof a
19 methyl v. an ethyl group,
H
\
H
/
.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. Brown, which he calls the "tool of increasing electron demand". 31
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 These
s^mthesized and preliminary rearrangement data were determined. were the series 5, 7, and 10 in which R = Me, Et, Ph, COOEt. CH R CH3O R Ph
Ph COH
R I C OH
CH/
0 7 10
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, ^ For
a competing methoxy fragmentation reaction occurs instead.
compound 5^, R = Et, ethyl migration is the major pathway (98%), but 2% of methyl migration also occurs, partial rate constant. Preliminary approximate rate data had been obtained for these rearrangements in trifluoroacetic acid. The results are dramatic allowing one to compute a
and unexpected, and are summarized in Table I.
Table I.
Preliminary Approximate Relative Rate of Compounds ^, _7, and 10 by NMR Spectroscopy^.
Series
R = Me R = Et 55 300 6
R e l a t i v e Rate R = Ph 26 R = COOEt 14 10,000 25 0.001
2
]_
10_
1 1 1
The rate data group were obtained byraeasuringthe 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 ofraethyland ethyl in . .. . j . 1 other systems,28,29,30 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 migration 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 ^
CH3O.
^R
OH
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. 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 Therefore much time was re-
of them (7a and 7b) are synthesized by one-step reactions frora commercially-available starting materials. In this section, the Credit
details of their preparation will be given individually. will be given to previous workers where appropriate.
The preparations of 4,4-dimethyl- and 4-methyl-4-ethyl-cyclohexa2,5-dienones ( 5 and 5b) have been reported previously _a 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. quinone (DDQ) or SeO The dehydrogenation with dichlorodicyano17 32 ' and are
both gave the desired dienones (5a and 5b) . These diselenides
35 The SeO^ method gives diselenide by-products.
can be removed from the dienones by recrystallizing from CCl^, but 24
25 RCHCH^^CHO + 'N H R (1) methyl vinyl ketone (2) piperidine acetate CH/ SeO/ or DDQ R CH/ A ^ R-C^CH^) = CH-N
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 modi3 fi The
fied from t h e synthesis of related compounds by Pleininger.
total synthesis of this compound is outlined in Scheme V I I I .
CH/ CH CH COOEt HCOOEt NA CH Piperidine acetate 0 Scheme VIII ^ CH.,CCOOEt 3 I I CHOH COOEt SeO, or DDQ 0 methyl vinyl ketone KO-t-Bu CH/ COOEt CHO
COOEt
5c
4-Methyl-4-methoxy- and 4-ethyl-4-methoxycyclohexa-2,5-dienones (7a and 7 b ) w e r e synthesized by t h e method of McKillop, 37 although
synthetic details for these specific compounds a r e not given by this author. T h u s , ^.-cresol or - e t h y l p h e n o l and thallium (III) nitrate
26 were dissolved in cooled (0C), 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 TKNO^)^
-^
OCH/
CH2CH3
0 11 R = CH3, 7a = C^H^, Tb^
In principle, the procedure for synthesizing 4-methoxy-4-carbethoxycyclohexa-2,5-dienone (]c) is similar to the route used for ^c38 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 A d distillation gave the cyclohexenone J^ in reasonable yield. step proceeded much better with DDQ than SeO^. this totai synthesis is outlined in Scheme IX. NaOCH CICH COOEt CH CH OH > CH OCH COOMe ^ - ~ > H CH3O ^ ^ ^ ^ CH,-C-COOEt methyl vinyl ketone pH8
^
The oxidation
The procedure for
CH OCH COOEt C00Et^^3 H CHO ^COOEt
Na
3 I I
CHOH 12 CH 0
+
0 14 COOEt
13 0 COOEt DDQ
>
CH3O
Piperidine acetate 0 15 Scheme IX
0 7c
The preparation of 4,4-dimethyl- and 4-raethyl-4-ethyl-cyclohexadienols (8a and 8b) are one-step reductions from _5 and _ b with excess 5^ 23 LiAlH, in dry ether. Both reductions are quantitative (98%) and As a matter of fact, the results in are actually
no further purification is necessary. literature 23
shows that attempted purification of ^ Both ^ and ^
extensive decomposition to o^-xylene. 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 excess LiAlH,
R = CH3, _5a = C^H^, 5b
R = CH3, aa = C^H^, _8b
It proved necessary to prepare 4-methyl-4-carbethoxycyclohexadienol (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 fnctionai 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 cleanly.
reducing agents were investigated and all failed to give ^
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 gave no reaction at
chloride hexahydrate (in ethanol) reduction alla
Lithium hydridotri _t-butoxy aluminate (in dry ether) reduction
gave the desired product (8c) but also produced up to 25% of the byproduct -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 other functional groups. Danishefsky 41 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). chromatography over silica gel gave pure ^ Dienols _ a , ^ , and ^ 9^ (76%). Column
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
OH 9
R = CH3, R = C^H^,
^ ^
R = COOEt, 9 _ c 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
^hbc(
l l ^3
l
'''^
> P h C cf
^. "CH3
H_0, dioxane
?^ OH
.0 3
^^ OH
9^3 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,2ethyleneglycol (lOc) was tedious and difficult, and was also carried 44 out by Rickey Gross and other undergraduates. the synthesis of this compound. The Reformatsky reaction of benzophenone and a-bromoethylpropionate afforded l,l-diphenyl-2-carbethoxy-l-propanol (16). DeScheme XI outlines
hydration was unexpectedly difficult, but could be carried out with
31 Ph
\ ( = 0 C
CH^CHBrCOOEt
-TTî >
Ph
y
Ph
Zn, Benzene
Ph I C I OH 16
Ph I C I H
COOEt
SOCl, Py
-^
Ph C = Ph C
\
CH, mcpba COOEt
Ph
\
/^3 Ô 18 COOEt
Ph
HCO Na - Ph ^
Ph
CH,
1 I - COOEt c c ocH m
IJ
0 19a Ph I COH
CH_ 13 + Ph C - C I I OH OCH Ph 0 19b
COOEt
JJ
NaOH
-> Ph
c
I
COOEt
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 Epoxide opening
but mostly starting material (17) was recovered.
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 _ a , _5b, and _5 in CF3COOH are 3,45_ dimethylphenol for _5a; 3-ethyl-4-methylphenol ( a . 98%) and 3-methyl^. 4-ethylphenol ( c _ 2%) for 2^; 3-carbethoxy-4-methylphenol for 5, (a. according to the previous study. Kinetic results from the UV
study and data thus obtained from further treatment are suramarized in Table II. From the equation developed by Waring of the rearrangement step depends on k , 26 , the rate constant (k^)
and the ratio of the
starting dienone and the protonated dienone ([B]y[BH ]),
k, = k ^ /
(1 +
[B^/^BH"^])
(Eq.
1)
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
33
c
O H 4-1 cO U O
a c
(U 13 C (U H
>3-
00 (Ti
CN
vO
O r-l r-( 1
CJ
O
vO
<u
03 CO rH vO
<X)
co
C O
<r iH
<r
o m CM
<J-
CN iH O iH
vO
o o o cn
ix:
O rH -H 1
U
O
f^J iH
co
vO CM vO
X
CVI
(U
<X)
^
00
c o
<r rH
VO iH fO
< !
CM rH
O
iH
o c
.H
(Ol
vO
03 0)
Qi H T3 C O
c o c
X
M aO
csi
00
O <y\.
(U cn
CN
(JN
cn
vO <r CN
r>-.
iH
vO
X 0)
o
iH
O >. O I
peS I
H 4J C O
c o
^ 00
a>
cO
O
%
B^2 00 <y\
4J
-(
00 H
(U
4-1
w o O o
(U
O >-/
4-1
cO
4-1
>.
w o o o
S I
U 0)
co
4-1
o c
(U
c
(U 3
4-1
4-1
B
(U 00
d cd
X)
s
(U

w O o
O (U
w
(U
(U
4-1
s
(U
w
(U
w o o o
(U
u u
cd
(U PC
o
0)
cfl H
c o
o in
u m
c o
aO in
CN
o o
CtJ
in
in
c a
34
spectrum compared to the values in CCl,, and the shift is related to

OT O" 7
the amount of protonation. H^SO^.
'
Complete protonation occurs in
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 ^ , _ ] , and _5) are only protonated in H SO, and show the ex5b 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 protonation, 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 _ can be calculated from 5 equation 2, in which
^D*^-O-U-^
^^^ ^ ^^^ ^^^ molar absorptivities of
B BH the unprotonated, protonated, and partially protonated dienones.
_ i l L _ z. flS
[BH+] ^ - ^B
^ .
(Eq. 2)
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+]
^ - \
' ' '
^^'
5a^, 5b, or 5c
Because trifluoroacetic acid does not protonate
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 to be
more was added, and at least 1.8% H SO, is required for ^ fully protonated.
The A^ values were.obtained in acetic acid soluThe calwas ^
tion, and A values were measured in trifluoroacetic acid. culations gave 56 + 1% protonation for ^ (the value for ^
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 ^ Waring's work, who found ^ and ^ and ^ is parallel to
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 _ a and ^^ both protonated a_. 57% in pure CF3COOH, which has a 5
/c OA
Hammett acidity function (H ) value of -3.30. that compounds 5a^ and ^
Waring
stated
followed the amide acidity function H^ However, no H^ values seem to be
within experimental uncertainty. 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 constant (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 However, since the NMR method is
protonation behavior is expected.
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 previous data (1:55:14) are somewhat different from
for the same dienones in the same solvent After
and at the same temperature as measured by NMR spectroscopy.
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 PÔ^ (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 PÔ^ 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 )
^\Compound Solvent ^ - ^ . ^ 10%^ 20%^ 40%^ 22.7

. 1
Observed R a t e C o n s t a n t (x 10 ) sec 5 63.4 4.85 11.4 139 31.2
97
O
.y
135
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, (CF300)^0
I +
y
-^
0-gCF
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. these conditions, ^ Under
and _5b rearrange at the same rate, suggesting The inductive effect of
that the first step is rate determining.
the COOEt group in _5 would be expected to depress this rate, as is observed.
(B) In Aqueous HSO, The rearrangement products for _5 and ^ the same as in CF-COOH. in aqueous H.SO, were
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 _ in 5 aqueous H^SO are given in Table IV.
39
o H
4J C O
>%
M
O .H
C (U
O O
cn a^
r^
O
a
H
c 
r-l
^ /
o m cn
m r^
o
f-^
r^ cn
o m co
XI
o <r r> m
CO
CN rH
\o
rH I
X
CN
 co
Cvj
P^ 00
CO
CN rH
cd <H
Cfl H
u o 4-1 o
x:
4-1
in
CN
vO
u o
I
CM
c o
O
CNl
ffi
Cfl
o cu co co x> o
m o
CN
m co ^ co
o
r^
C3^ CN CN
r^ r^
CN 00
<y\
T3 (U 4J
o
(U U U O
o 
00
a
3 O
<y\
4J
Vw/
CO cd
4-J
cO O (U
ml c n
c O
c o c
(U .H Q
(U
u o
w o o o
4J
>-
JC
5 CM
(U 3 (U
CO
4-i
c 5
s
8^2
o
00
O vO
13
m co m
XI
cd
sr o
o m m
c
H 4J ct3 $-1 H
c

CH
y
COOH + CO/
OH
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. Waring 28 has reported a full set of k , and k^ values of 5a and obs 2 Therefore this protonation behavior can be cal-
_5b in aqueous H-SO,.
culated by incorporating his data for various concentrations of H_SO, into equation 1. It was then calculated that _ a and ^ 5^ both undergo
ca. 60% protonation in 52% HSO, ; ca. 90% in 61% H,,SO, , and ca. 99% f 2 4 2 4 Et in 70.4% HSO,. 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. Vitullo 47
It was therefore necessary to try to estimate it. 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, H+ CH
\
CHCl,
I
0 21
0 21+
Table V.
Protonation of Compound 21
Wt. % H/,SO, 2 4 47.38 52.47 55.42 58.95 62.60 67.01 70.44 72.96
n^^ / 11
0.038 0.0680 0.105 0.165 0.326 0.734 1.80 3.07
-H
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^, The inductive
a. 20% in 60.8% H^SO^, and a. 64% in 70.4% H^SO^. 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 substituent, it is not unreasonable to predict that _5 would have somewhat 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 HSO, 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 protonation 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 route.48 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,
OCH, OCH. 22 23 OCH/ 24
The kinetic results of rearrangements of 2 . 2^ and ]c^ in 1:1 a 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 rearrangement 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 araassspectrum 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 rearranged product and oxygen in the air, and can be avoided by monitoring the reaction in an air-free cuvette.
44
>^
T3
o C 
c O O
LP
o o o o
ro
<r
CO
258
*\
o o o
xi
M
o x: 4-1
(U
o c
H
e e H
(U
c o H
4-t
C
4-1
x: c
co
OJ
3 H O 00 U -H
a c o
(U
4J
w o o o
^
T3 C U
4J
cu
c
6
c
(U 3 4J H
4J
(U
r^
o 
3
C/0
w o o o
c O
>-(
u a
(U
o 
(U r-l X5 CO
c 3 o o o
H
4-1
c o
O
(U 4J c O
Cu
coj r^l
-^l r^l
^l r^l
O c O (U ct:
c O
45
OCH CH,
OCH/
OCH/
OCH/
_25 Again, the NMR method was used to estimate the protonation behavior of dienones ]_, and was estimated a_. 27% protonation for â. (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 _ are presumably due to the inductive effect influence 5 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 protonation behavior found for series _ in CF3COOH. 5 These values were taken into account for calcualting k the migration tendency thus obtained for M^^jj^ : M ^ :M^^ for dienone ]_ in CF3COOH/CH3COOH. values and
= 1:620:57,000
(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 ^* 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 HSO 2-^4 Compound Substituents Group Migration
Ta.
k , X 10" obs . . sec 4.3 1270 7850
Ratio of obs 1 295 1830
Me, MeO Et, MeO COOEt, MeO
Me Et COOEt
Tb
7c
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 rearrangements were over (especially for 7c). 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 Therefore, no precaution was
of k ^ , but not the migration tendency is given in Table VII. Howobs 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 If the dienone is protonated to
COOEt ' to M^jj in CF3COOH which is 57,000.
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-Cyclohexadenols (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
_ OO
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 constants 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 spectroscopy 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
<H
49
X3
ai!
o o TA
co o
00
CO
o o
s
/~\ Q
s^/
CM
1
C O
CN
1
co
O
1-i
rH
1
>^
1
00
C
H
4-1
rH
o
rH
o
X
o
X
-
o
3
CM
rH
o
1-i
X
CO
II
T-\
tc a
o
0>
o
CM
r-l
<y\
<y\
o m c^
4J
cO CO
co I
CN I
c o
o
o
X
CN
II
ffi
o
CM
o <r
o
co
4-1 3 >H O
co
c o
H 4-1
00|
< ^
r-l
TS
o
C/3 O H
c O
^
PQ CO I
H O
<d
co C
vO I
'^l ooj
M
C0|
< u u
c O (U
o
00 1
Cfl r-l O
CN
H 4J
X
CN
X
00 CO
X co co
oo| u
O
<H
3 c o
r-l
o
Cv4
Csl
C O
4J
4J
S o
o
C/3
\o
c
(U H Q
c O
4J Cfl
rH
co
4J
4-1
o o CU
u u
U
rH
>
X5 cO
C O X3
< u
c O
u < u x:
H
50
migration). Et (M
It was also found that pinacol lOb shows the same result
= 54; methyl migration a.. 2%, ethyl migration a.. 94%; this Thus, it is
will be discussed later) in H^SO,/HOAc/HÔ media. reasonable to predict that ca. 4.5% of the k , obs
value in 8b (see
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
^
^
CH/
R H
^-1 OH 8 8
^-2 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
ôbs ^^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 ^ _ _ the _ and"]_series. 5 From the spectral parameters published for 5,5-dimethyl-l,3value (21.1) is also smaller than in
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-
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
tion was faster than the rate of rearrangement.
ion is depressed for 8c_ by an unknown amount due to the inductive effect of the carbethoxy group, the ratios of isomerization to rearrangement 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 ^ and ^ were very similar [t .. ca^. 60 sec in solution (A) and (C) ], ,
was much slower (estimated to require 5 days for completion However, the decomposition of ^ was
in aqueous HCl, pH = 0.66).
complete within 2 minutes in CF-COOH. The decomposition may be
R
H"^, - C H OH
+
\ <
CH3OH
H 9*
OH
9a., R = CH3; fb, R = C^H^
concerted instead of going through the cation, since an a-cation adjacent to COOEt is very destabilized. 19 23 * 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-diphenylbutanone (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 1 C 1 OH CH_ I3 C CH I 3 OH ^, Ph Ph ^ X O^ C ' ^ CH3 26 Ph I C > CH3 27
Ph
>
CH + ^
Ph
^CH C^ "Ô
lOa
Ih
^
^ _H_= Me
^" " ""Me e, - e

Ph 00
(Eq, 4)
54
Figure 1.
8 12 16 20 time (min) , Plot of log (Aoo -A) vs. time for iOa in CF^COOH/ CH COOH at 25
55
UJ
CO T3
o H
(^
4-1 C O
C O r-l
m
00
o o o
cOJ
CJ|
sO
o T-\
X
O r-{ 1
0\
00 T3 O CM 00 CO
.
..bJ
Cfl
.
rH
,-\
o DC o o o
c
H
/^
/s
co W O
00 H 4-> C O M 00 H
^S -dCT\
N w
00 r-l
N ^
^s
4J
W
/\
^S r-l
x:
/-s
pu ^
. <
Cfl r-l
o o c
CN 00
^w'
&
cO
.H
ru
<H
o u o
O, 3
^ / ' ^
c 1 '^ O o ^s
m w
CO
P C O
CO aC aC PL,
4J [xl O O O
cO O r-i
U
C O O r-l
!-l
o
Cfl 4-1
x:
C O 4->
<H 4J U
<H
p^
M
c <u B <u
c
u u
X!
PH
aC
(1H
00 cO
4J .H 4J C O
aO
C c u 3
4J
co
*
4J
o o
33
0\
w
\
co
w o o o
M
c O
4J U cO D. 73
O O <U
4J C O
u .H
<H (U
CO
co
C/3
cO <U pci
ffi
ffl
c o
<U
x: 4J
MJ
x: 4J
"H O C O X3 0
X
<U
X3
CO
X)
o a S o o
C 3
o
O rH
c O
aO
O rH
o ol rc o
C 0 - i3 D <
CO
w a
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 51
ave. 0.22 + 0.01. ^ e , and e values from Schubert's publication; _ Ph Me
e , is the molar absorptivity of 26, and e., is the molar absorptivity ph Me of 27.
e
00
is the molar absorptivity of glycol solution after raore
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 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
u o
(U
3 U
co
CN
(U
!-i
3 00 H
58
o
ffi O O
! O
oco
ffi
o ffl o o o co w o c
H X) O
c
(U
s

r-l
S
4J _o .
o co
o o
3
!-(
(U P
4J
L-
a
o
Nl
C cu
00 c O
cu
>-l +J M-l H
o o S
o eo
3 5-1 4J O CU
Cfl
co
<u x:
4J
5-1
<U 4J <H
cO
_J
CO
(U
J-i
3 00 H
59 product (2^); the singlet at 6 3.62 was the methyl peak of the methyl migration product ( 3 ) ; and the big singlet at 6.43 was the methyl _0 peak of the ethyl migration product (28) . Therefore, integration of these three singlets gave the ratio of CH^Êt^Ph migration of lOb as ca. 1:94:5.
Ph C, HI I3 Ph C C Et I OH OH lOb
>
Ph , ph C I Et 28^ ^^ C^ Ô
CH C^ Ô ^ +
CH Ph^^3 >C O^ ^ Ph ^
C -- Et
Ph
I C I CH3 30
The break line of the log (A sistency of ratio of k ,
- A) v_s. time plot and the incon-
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 spectroscopy. COOEt 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 I I Ph C C + I OH 31 a, R CH3; b, R Ph R I I Ph C C CH 1 ^ 3 OH 32^ COOEt
CH, 3
C^H^; c, R
60 Cation 21 is more stable than î since the positive charge is on the benzylic position. product. This cation can give the R or CH migration
Especially when R = COOEt, this substituent destabilizes
cation 22 greatly and therefore COOEt migration is the only process. 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 solution (F) (H^SO^-HOAc-HÔ, 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 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. available for the rearrangement.
>.
O
'T3
c . ;..,
(U
61
>
H
O H
4J
o
rH
o -cr m
cu ,o
O 4J
T3 -i
O rH
^S CN
a
">/
<0 rH
00 H
S
CX, 3 O -i
s-s
c O
W
,N
o o
>./
o co
&-?
LO
V/
c O H
co P C
ffi
PL,
x:
PH
>H O C O
4J
C O
4J
rC
rH C O
(U
p->
#v
x: p-i
4J
>
eha'
XI
X5 CM 00 rH
x: 4J
<H
ich is asi
x: :$
H
C O IJ 00 H
s D
u o
>
O H 4J c O
C O
0
4J
>-l
(U
u o
( -
X) 3 co
CO
>
C O
4J
ffi
w cx
.ii
tO O r-l
X3
(H
U O <H
T3
 H
C O
O P-
C 3
c O X3 CO
U
Cla r-l H
o r-l
o rH
c O
S O o
.^
tO
co
62
o
X
<
o
X I
o
X
<r
C/D CM
XI
o
4J
c H
HO O

rH O
O 3 O U
co <u
a
N
4J
c
(U 00 cO (U
5-1
o o S
3
5-1 4J
CD
n
x:
4J
S-i
(U
O <U Cl.
co
(U
C O
cu
5-1
3 00 H W
63 The rearrangement step was proved to be the rate determining step for lOa
CHo
(and presumably also lOb). Therefore, a comparison

FtFt*
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 _ 0 = . 50) . This 3^ 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.
64
Table XII.
Summary of Migration Tendencies.
Series
Rearrangement Conditions
CH3 M CH,.
Et M CH,
COOEt CH/,
CF3COOH (25) CF3COOH (45) Aqueous H.SO, solutions
1 1 1
103 98 49
24.7 23.4 i ca. 10
1:1 CF3COOH/CH3COOH Aqueous H,^SO, solution
1 1
620 295
57,000 57,000'
HCl buffer solutions ( A ) , (B), (C), and (D) (pH= 1.83-2.34
21.1
10
Solution (F): H_SO,:HOAc: HÔ 2 " ^ 45.0:17.0:38.0
53
These values are estimates, due to the difficulties in measuring the protonation behavior. See the text. 'only decarboxylation takes place. In CF3COOH/CH3COOH, the rearrangement 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 by its substitution pattern, and on the medium. 28
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 [B]/[BH
step k-, data to satisfy equation 1, k = k , (1 + _ 2 ^ 2 obs to be obtained.
]), has
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 because 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 theraajorfactor 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; (ii) The dienone ring is planar 53 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. out 26b It has been pointed
^ 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
R C
>
C ^
I
R'_-C
I
C +
1
R C
1
C
l' -
- l
- l'
A further problem
the central CC bond relative to rearrangement.
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 transiacidity function, and that
tion state for rearrangement follows the H

is.
0 exchange occurs at the benzhydryl oxygen in 0 (the solvent he used was H SO,/HOAc/HÔ).
enriched solvent
68 This, combined with the stabilizing influence of the phenyl substituents on the classical carbonium ion (33) before the rearrangement, suggest that a substantial charge density is involved in the transition state in H^SO^/HOAc/HÔ 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
OH
+^Ph
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, and 34c) were prepared
60
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 t h a t in Scheme XIV ring-opening of 3 ^ generates the same cations (10 ) as the pinacols lO^ do in a c i d i c medium, and the r e l e a s e of the s t r a i n for the three-member ring enhances the ionization r a t e f or _34_. The i o n i z a t i o n i s e s s e n t i a l l y an i r r e v e r s i b l e process because
i t i s highly unfavorable to regenerate 34 from the s t a b l e ion 10 .
69
/CH3 ^C^-yC^
H+
l>
P. Ph C -
CH3 OH
%fO, ^
^...3
^
R
> Ph 3II 0
C -
C OH
P^
+
10 +
CF.3C-O
34
35
^2
ph Ph c c
CH3
I
R
\
0
a , R = CH3; b , R = C^H^; c, R = COOEt. Scheme XIV For 3 4 a , a very f a s t r a t e was observed for approximately t h e f i r s t h a l f of t h e r e a c t i o n , followed by a much slower r a t e when t h e format i o n of t h e product 36a was monitored. The r a t e c o n s t a n t for t h e f i r s t
p a r t of t h e rearrangement i s too f a s t to follow by U spectroscopy. V However, t h e slower r a t e c o n s t a n t i s estimated to be a.. 1.86 x 10 sec . C l e a r l y , t h e c a t i o n lOa -4
p a r t i a l l y r e a r r a n g e s to 36a, and i s
p a r t i a l l y t r a p p e d by CF3COO the t r i f l u o r o a c e t a t e to 36a.
(k^) followed by r e i o n i z a t i o n (k _) of which can then r e a r r a n g e
(35a) through c a t i o n 10a
Thus, k_3 i s t h e r a t e determining s t e p for t h e l a t t e r p a r t of Since t h e c a t i o n 10 i s formed i r r e v e r s i b l y from 34,
the reaction.
k^ must be comparable in s i z e to k/., and both a r e f a s t e r than k, , which i s t h u s r a t e d e t e r m i n i n g . For 34b, t h e rearrangement i s complete in seconds. T h e r e f o r e , no
k i n e t i c d a t a a r e given and k , i s e s t i m a t e d to be b i g g e r 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 t h y l i s i n h e r e n t l y a much
b e t t e r m i g r a t i n g group than methyl (product a n a l y s i s of lOb s u g g e s t s t h a t e t h y l i s approximately 94 times f a s t e r in m i g r a t i o n as compared t o methyl i n t h i s system in a CF3COOH/CH3COOH medium) and t h e m i g r a t i o n i s complete b e f o r e t h e CF-jCOO lOb . Thus, k, i s r a t e d e t e r m i n i n g . For 34c (R = COOEt) , t h e k ,_ v a l u e i s 4.62 x 10 obs -3 sec -1 . The s p e c i e s can r e a c t with c a t i o n
UV and N R s p e c t r o s c o p i c d a t a suggest t h a t t h e i o n i z a t i o n ( k , ) i s t h e M r a t e - d e t e r m i n i n g s t e p ( r . d . s . ) and a g a i n , 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 p r o v i d e s evidence t h a t COOEt i s
a b e t t e r m i g r a t i n g group than methyl but t h e exact m i g r a t i o n tendency i s unknown. Note t h a t k. i s d e p r e s s e d , as compared to t h e v a l u e s of ) , by t h e i n d u c t i v e e f f e c t of
34a and 34b ( t o o f a s t to measure, >10 t h e e s t e r group.
Applying t h i s d a t a to t h e p i n a c o l c a s e , t h e mechanisra of _10^ in CF3COOH/CH3COOH can be w r i t t e n as shown in Scherae XV. H+ Ph
Ph
CH_
1 ^R c ic 1
OH OH
CH/. Ph 13 1 C R C 1 + OH
CF3COO" ^3 ~ ^ 3 .
Ph
CH_ Ph 13 1 C C R 1
CF3C-0
u
OH
1
10+
>/
11
^2 CH3
Ph
Ph 1 1 C 1 R
'ô
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 fore k_3 for the i o n i z a t i o n of 3 5a.
sec
) and i s t h e r e -
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, p s e u d o - f i r s t - o r d e r k i n e t i c s were observed (k ,
obs -2 -1 X 10 sec ) . This must be due to the ionization of lOb (k,) . Again,
=1.96
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. For lOc, k , was 4.80 x 10 obs 6 sec 1 . Again this is a measure
of k^ , which is slowed down by the group.
inductive effect of the ester
From the discussion presented above, it is conciuded that the migration tendencies follow the order that Et^COOEt^CH^, with the M-. value ca. 94 times bigger than ^ ^ ^ , Cn3 Ln3 .. as judged by the product Since in no case is
ratio of Et to Me migration in compound lOb.
the r.d.s. the rearrangement, it is impossible to determine migration tendencies for this system in CF3COOH/CH3COOH.
72
T r a n s i t i o n S t a t e s f o r Dienone and Dienol Rearrangement In e i t h e r t h e rearrangements of t h e dienones (_5 and _7^) or t h e d i e n o l s (8^ and 9_) , one can r e p r e s e n t t h e rearrangeraent s t e p 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
r e a c t i o n of dienols 8 are complicated by the ambiguities connected ^ with having a leaving group (HÔ ) to draw off some of the charge d e n s i t y , but presumably the highly resonance-stabilized 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 r a t e s is v a l i d . 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 tZl
center i s s t a b i l i z e d by s t r u c t u r a l modification.
H. C. Brown It is
termed t h i s as the "tool of increasing electron demand". now supported by a great deal of data. by Gassman and Fentiman
However, the o r i g i n a l study
on the anti-7-norbornenyl system pro-
vides one of the best examples for the present case. Thus, these authors observed that the r a t e enhancement by the double bond of 10 observed in the parent secondary system decreases
with the introduction of s t a b i l i z i n g groups at the 7-position (38)
74 and effectively vanished with the ^-anisyl group.
OPNB
OPNB
PNB = -nitrobenzoate 38 Z = 7-H 3,5-(CF ) -CF 2-H ^-CHÔ 1.00 1.00 1.00 1.00 1.00 11 10 255,000 34,000 41.5 3.4
8.0-1
"^ "ô-OCH
4.0^..
log ( z) 0.0
E-CF^-^ 4.03,5-(CF3)2-^
8.0" -1.0 0.0 1.0
-2.0 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 c o n s t a n t p+ , from t h e r e l a t i o n s h i p , log (k /k^) = + + 57 ^ P C , 7 p r o v i d e s a convenient measure of t h e e f f e c t . The p value
f o r 37_ i s - 5 . 2 7 ; f o r 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^)^, t h e behavior of 2 1 p a r a l l e l s 3_Z. ( s e e F i g . 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 substituent 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 Does the MEt value for each system reflect this trend? proposed postulate valid? The results suggest the answer is positive. The M Et value Is the
(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 The second question is, can the H^^

Ft-
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 This means, when the
Et COOFi" ^CHo " ^^^' ^CH ^ 57,000 for dienones ]_.
migration tendency of ethyl is small, migration tendency of carbethoxy 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
is small; and vice versa.
XII in Results section). An interesting comparison was made between the dienone _ and 5 Et the pinacol 10. Thus, the M^
L.n.T
value is 50 for 5, and 53 for 10 in
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 _^ in CF3COOH. 5 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 At least the
to be this ionization, not the rearrangement step.
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 _ were chosen to investigate the temperature 5 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 someL.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 Again, a factor of 2 is
on migration tendency in both systems.
considered a small change and it is hard to draw any certain conclusion. It seems that the migration tendency is somewhat "inert" Presumably this is largely because
to the identity of the solvent.
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 arainorcontributor. In fact, instead of rearrangeraent, fragraentation via an
1. . . 59,19 acylium lon occurs m extreme cases. Ov /OEt oX /OEt 0+ OEt
%-^
r. 39 c^ ^C
^c^
= C ^ 40 41
\c/
^C
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 i bond of the r 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 migraCH3 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 rearrangement 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 General A l l r o u t i n e NMR s p e c t r a were run on a V a r i a n A-60 o r 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 . chemical s h i f t s a r e r e p o r t e d i n u n i t s d o w n f i e l d from A l l NMR internal
fTTW
reference TMS.
Infrared spectra were obtained with a Beckman AccuLab
8 as a thin film or in CHCI3 solution. All melting points are uncorrected 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 extraction 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 20-30ramHg. 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 treatment 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 firstorder rate constant was extracted. The rate constants were deterThe standard devia-
mined based on 3 runs, unless otherwise stated.
tions were calculated by a Texas Instruments SR-51A calculator. Preparations of 4,4-Dimethylcyclohexa2,5-Dienone (5a) and 4-Methyl-4-Ethylcyclohexa-2,5-Dienone (5b) The precusors of _ a and _ b , 4,4-dimethyl- and 4-methyl-4-ethyl5. 5^ cyclohexenones, were prepared by the methods of Benzing Vitullo, 33 and
and were synthesized by the undergraduate workers in Thus, 4-methyl-4-ethylcyclohexenone (2.98 g, 22
this laboratory.
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 _ a followed the same route as _ b , using isobutyral5, 5^ 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-Carbethoxycyclohexa-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-Methoxycyclohexa-2,5-Dienone(7a)
^ ^.:^^^.,_-^
^
-.. ^
^ ^^_.:
/.
A solution of thaliium (III) nitrate (TTN) (0.5 g) in dry îethanol (250 ml) âs added to ^stirred; cooled (0 C) solution of the p-cresol (2.6 g, 24 mmol) in methanol (50ral)'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 â, m.p. 60-61C. 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-Methoxycyclohexa-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 The NMR spectrura shows peaks at 60.83(3H,
crystalline Tb^,ra.p.62-65C.
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-Carbethoxycyclohexa-2,5-Dienone (7c)
c
(A) Preparation of Ethyl Methoxyacetate Ethyl chloroacetate (613 g, 5raol)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 obtain 254 g (2.15 mol, 43%) of etheylraethoxyacetateb.p. 125-130C.
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. Theraixturewas stirred for 1 The
day, and a brown precipitate formed as the sodium disappeared. 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, 9599C) to collect 56.5 g (23% frora ethyl methoxyacetate) ethyl 2-formyl2-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-Methoxy5-Oxocaprate Ethyi 2-formyl-2-methoxy-5-oxocaprate (43.76 g, 200 mmol), piperidine (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-carbethoxycyclohex-2-enone (15) , b.p. 100-105C (0.4 mm) . The NMR spectrum shows peaks at 1.17(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-Carbethoxycyclohex-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 refluxed 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 600ragof white crystals m.p. 60-62C. The NMR spectrum shows peaks at l.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). C, 61.22; H, 6.16. Found: Anal. Calcd. for
C^QH^^*^^
C, 61.01; H, 6.22.
Preparation of 4,4-Dimethylcyclohexadienol (8a) and 4 - M e t h y l - 4 - E t h y l c y c l o h e x a d i e n o l (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 â. The NMR spectrum shows peaks at 1.02(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 Ê, using _ b as 5^ starting material. The yield was 99%. The NMR spectrum shows a ca.
1:1raixtureof 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-Carbethoxycyclohex-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. volatiles were

7 3 .
The organic phase was dried over MgSO, and the in vacuoThe residue was chromatographed
on a / X - m . column of silica gel using 15% ether-petroleum ether g to yield 312 mg (76%) of 8. The NMR spectrum shows a a. 1:1 mixture 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-Methoxyand 4-Ethyl-4-Methoxycyclohex-2,5Dienols (9a and 9b) Compounds â^ and 21 were prepared following the procedures for â^ 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 â 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-Carbethoxycyclohex-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 _ a , _52, and 5 were carried out in CF/,COOH 5, and in varying concentrations of aqueous sulfuric acid, and the resuits will be discussed below.
Rearrangement of 4,4-Dimethylcyclohexa-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 product, and k , thus obtained was 6.82 + 0.10 x 10 _ obs and 4.92 + 0.15 x 10~ (B) In Aqueous HSO, The rearrangement product is 3,4-dimethylphenol, as reported. * The rearrangement was determined by monitoring the increase in UV sec~ at 45C. sec at 25 C,
90 absorption at X 276 nm due to the formation of these products, and the \ b s ^^^^ obtained was 1.35 + 0.05 x 10~^ sec~^ in 60% (by weight) aqueous H^SO, at 25C.
Rearrangement of 4->fethvl-4-Ethylcyclohexa-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 25C, and 2.46 + 0.08 x lO"-^ sec""^ at 45C. (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 monitoring the increase in UV absorption at X 276 n a due to the formation of r -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~^ s c ' " in 60% (by e~' weight) H^SO, (Aq) solutions at 25C. Rearrangement of 4-Methyl-4-Carbethoxycyclohexa-2,5-Dienone (5c) (a) In CF3COOH The rearrangement product is 4-methyl-3-carbethoxy-phenol max 255 nm). (X
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 25C, and 6.17 + 0.10 x 10~^ sec~ at 45C.
(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 solution. 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 to the reaction is
50 ml of aqueous H^SO, solution and stirred at 25 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^, respectively.
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-Methylcyclohexa-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. 2 4 The results are discussed below.
(A) In 1:1 ratio of CF3COOH/CH3COOH The rearrangement product was identified as 3-methyl-4-methoxyphenol 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 7 _ was weeks in this medium, so a Guggenheim a 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 kobs in this medium was 1.27 0.02 x lO"^ sec"''' at 25C. , + Protonation of ^fethoxy Dienones (7a, 7b, and 7c) in 1:1 Ratio of CF/,COOH/CH.,COOH J J Methoxy dienone _ a was treated in the same fashion as described 7. 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 unprotonated and fully protonated forras, it was estimated a_. 27% protonation 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 i i 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 concentration 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-Dimethylcvclohexadienol (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 < 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.^-^ ôbs ^ ^^^ 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-Ethvlcyclohexadienol (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
X 10
, 1.40 + 0.05 X 10" , 1.01 + 0.35 x lO"
sec~ at 25C, respec-
tively. Rearrangement of 4-Methyl-4-Carbethoxycyclohexadienol (8c) The rearrangement product of 2 was shown to be -carbethoxytoluene 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 25C, respectively. The isomerization product of 2 6-methyl-6-carbethoxycyclohexa2,4-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-Cyclohexadienols (9) Monitoring 4-methoxy-4-methyl- and 4-methoxy-4-ethylcyclohexadienol ( 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~^ s c " " for 9a; e^" 2.94 + 0.11 and 1.24 + 0.05 x lO"^ s c " " for 21 and the products e"' from these two reactions show very similar UV spectra (X = 275 and max 284 nm for â; 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 The reaction of 21 ^^ weak acidic Reaction of 2 with CF3COOH Instead of rearrange-
which identified as _-ethylphenol.
solution (A) shows the same product.
gave _2^-methylphenol according to NMR spectroscopy.
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^-carbethoxyphenol 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-Methyl1.2-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 - HÔ, 45.0:17.0:38.0) at 25C. The results are discussed below. The rearrangement products in these two acidic media were 3,3diphenyl-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 25C. The phenyl v. methyl obs migration ration was 0.135 j 0.005. f Rearrangement of l,l-Diphenvl-2-Methyl1,2-Butanediol (lOb) The rearrangement products of Ôb 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~^ s c - " in solution (F) at 25C. e^' 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 extracted 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 thisraixtureshowed mostly ethyl migration product (28) (see Fig. 2, page 57). In order
to sort out the ratio of these products, NMR shift reagent, ResolveAl 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% methylraigrationproducts (see Fig. 4, page 62). Rearrangement of l,l-Diphenvl-2-Carbethoxy1,2-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 spectroscopy. 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 25C. This compound obs
99
undergoes slow decarboxylation in solution (F). Therefore, no measurement of the rearrangement rate was possible. Rearrangement of Epoxides 34a, 34b, and 34c The rearrangements of epoxides _ 4 were carried out in 1:1 ratio 3_ 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 However, the second part's rate constant is 1.86 + 0.04
spectroscopy. X 10 sec
Compound 3^ in secondsa
rearranges so fast that the reaction is complete
Thus k-, is estimated to be >10 sec . Ibs Compound V^ was monitoring the product (36c) formation at 263 -3 -1 and 285 nm, and k thus obtained was- 4.62 + 0.21 x 10 sec . obs
LIST OF REFERENCES
^'
^^^ f-;/; n ^ f ' ^"^ ^' ^^^' ^^- "Molecular Rearrangements, Part I, Interscience, 1963, pp. 1-25(b) D. Bethell and V. Gold, "Carbonium lons, and Introduction," Academic Press, New York, 1967, pp. 204-211. H. 0. House, J. Am. Chem. Soc., 22, 1235 (1954). H. 0. House and D. J. Reif, J. Am. Chem. Soc, 77, 6525 (1955). H. 0. House, J. Am. Chem. S o c , 22 2298 (1956). H. 0. House and R. L. Wasson, J. Am. Chem. Soc , ]9_, 1488 (1957). 2490* ( ' ^ ^* ^* ^^^^* ^ ' ^ ^* ^* ^^^^''' ^- ^ - ^^^"^- S^-' Zl' ^'^' '' H. 0. House and D. J. REif, J. Am. Chem. Soc, _79, 6491 (1957). H. 0. House and G. D. Ryerson, J. Am. Chera. Soc , _82, 979 (1961). H. Plieninger and T. Suehiro, Ber., 2798 (1956). S. Inayama and M. Yanagita, J. Org. Chera., 2 . ^^65 (1962). Z R. H. Churi and C. E. Griff n, J. Am. Chera. Soc, 22 ^824 (1966). M. Sprecher and D. Kost, Tetrahedron Letters, No. 9, 703 (1969). Y. Pocker, Chem. Ind. (London) 332 (1959). M. Yanagita, S. Inayama, M. Hirakura and F. Seki, J. Org. Chem. , 22 690 (1958). N. L. Wendler, in P. de feyo (Ed.), M lecular Rearrangements, Part 2, Interscience Publishers, New York, 1028 (1964). R. B. Woodward and T. Singh, J. Am. Chem. Soc , 22 ^^^ (1950). J. N. >ferx, J. Craig Argyle, and Lewis R. Norman, J. Am. Chem. S o c , 26, 2121 (1974). (a) V. P. Vitullo and N. Grossman, Tetrahedron Letters, 559 (1970); (b) V. P. Vitullo, Chem. Commun., 688 (1970); (c) V. P. Vitullo and N. Grossman, J. Am. Chem. Soc, 2^, 3844 (1972). J. N. Marx and E. J. Bombach, Tetrahedron Letters, 2391 (1977).
2. 3. 4. 5. ^' 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
19.
100
101 20. For a summary and leading references, see: P. Brownbridge, Pa Ka oo-^^f^^"''' ^' ^^^P ^'''^ ^' W^^ên, J. Chem. Soc, Perkin I, 2024 (1976). (a) E. C. Friedrich, J. Org. Chem. , 22 ^ 1 (1968); ^3 (b) V. P. Vitullo, J. Org. Chem., 21 224 (1969); (c) K. L. Cook, M. J. Hughes, and A. J. Waring, J. Chem. Soc, Perkin Trans. II, 1506 (1972). M. S. Newmann, D. Pawelek, and S. Ramachandran, J. Am. Chem. S o c , 21 995 (1962). V. Pa Vitullo, M. J. Cashen, J. N. Marx, L. J. Caudle, and J. R. Fritz, J. Am. Chem. S o c , ÔO, 1205 (1978). M. Stiles and R. P. >feyer, J. Am. Chem. Soc , 21 1^97 (1959). P. D. Bartlett and Thomas T. Tidwell, J. Am^ Chem. Soc, 90, 4421 (1968). (a) M. J. Hughes and A. J. Waring, J. Chem. Soc, Perkin II, 1043 (1974); (b) J. W. Pilkington and A. J. Waring, ibid., 1349 (1976). (a) J. N. Marx, Tetrahedron Letters, 4957 (1971); (b) N. C. Deno, H. G. Richey, N. Friedraan, J. D. Hodge, J. J. House, and C. 0. Pittman, J. Am. Chem. Soc, 22 2991 (1963); (c) R. J. Zalewski and G. E. Dunn, Can. J. Chem. , _42, 2264 (1969); (d) G. A. Olah, Y. Halpern, Y. K. Mo. and G. Liang, J. Am. Chem. S o c , 21 3554 (1970); (e) V. P. Vitullo, J. Org. Chem., 21 224 (1969). J. E. Dubois and P. Bauer, J. Am. Chem. Soc, 2^ ^ÎO (1968). Ra L. Heidke and W. H. Saunders, Jr., ibid 21 ^^^6 (1966). T. Yvernaut and M. >fezel, Bull Soc Chim. Fr., 638 (1969). H. C. Brown, "The Nonclassical lon Problem," Plenum Press, New York, N. Y., (1977) . A number of undergraduate students prepared these samples. E. Benzing, Angew. Chem., 2i 521 (1959). V. P. Vitullo, J. Org. Chem., 21 3976 (1970). John N. >ferx and Lewis R. Norman, Tetrahedron Letters, 2867 (1973)
21.
22. 23. 24. 25. 26.
27.
28a 29. 30. 31. 32. 33. 34. 35.
102 36,
(a) H. Plieninger, G. Ege, H. J. Grasshoff, G. Keilich, and W. Hoffman, Ber., 2 1 , 2115 (1961). ^^^ l' ^}^^^^''^^ll ^ ^^^1^' R- Fisher, and W. Hoffman, ibid., 2 1 , 1774, 1765 (1965).
37.
^10^^"^"^"^^* * " ^^'"''y* (197 6).
^""^ M. Edwards, J. Org. Chem., 41, 283
38.
This compound was prepared by Danny Peckenpaugh, John Mbntgomery, and Reza Fathi in this lab. Jean-Louis Luche, J. Am. Chem. S o c , ÔO, 2226 (1978). S. Krishnamurthy and H. C. Brown, J. Org. Chem., _40, 1864 (1975). S. Danishefsky, K Hirama, N. Fritsch, and John Clardy, J. Am. Chem. S o c , 101, 7013 (1979). These compounds were prepared by Rickey Gross, Russ Hill, Terry Thames, and Bennie M:Williams in this lab. C. L. Stevens and C. T. Lenk, J. Org. Chem., 22, 538 (1959). Rickey Gross, Russ Hill, and some minor contribution from a number of undergraduate students in this lab. H. H. Hyman and R. A. Garber, J. Am. Chem. S o c , 21 1847 (1959). Robert W. Taft, Elton Price, Irwin R. Fox, Irwin C. Lewis, K. K. Andersen, and George T. Davis, ibid., 85, 709 (1963). V. P. Vitullo, J. Org. Chem., 21 224 (1969). This experiment was carried out by Elizabeth Hall and Patsy Woods in this lab. This dimer was synthesized by Nim Batchelor in this lab. C. W. Spangler and P. L. Boles, J. Org. Chem., 3]_, 1070 (1972). W. M. Schubert and Paul H. LeFebre, J. Am. Chem. S o c , 2 1639 (1972). (a) K. L. Cook and A. J. Waring, J. Chem. S o c , Perkin II, 84 (1972). (b) K. L. Cook and A. J. Waring, ibid., 88 (1972). E. A. Guggenheim, Philos, >feg., 2 ^^^ (1926). G. S. Hammond, J. Am. Chem. Soc., 77, 334 (1955).
39, 40. 41.
42.
43. 44.
45. 46.
47. 48.
49. 50. 51.
52.
53. 54.
103 55. 56. 57. 58. 59. 60. P. D. Bartlett, Nonclassical lons, Benjamin, New York (1965). W. J. le Noble, Highlights of Organic Chemistry, M. Dekker, New York (1974). P. G. Gassman and A. F. Fentiman, Jr., J. Am. Chem. Soc, 92, 2549 (1970). H, C. Brown, M. Ravindranathan, and C. G. Rao, J. Am. Chem. Soc , 100, 1218 (1978)a S. Danishefsky, C. F. Yan, and P. M. McCurry, Jr., J. Org. Chem., ^ , 1819 (1977). These corapounds were prepared by Rickey Gross and Benne McWilliams.
APPENDIX
Guggenheim
fethod
104
105 k For a f irst-order reaction, C -kt > 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
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. made at times t , t A-^, A' ^feasurements A-, A_, A^, . . . are absorptions t/., . . ., and a second series of measureraents
A,^, . . . are made at times t^ + A, t^ + A, t^ + A, . . ., For accurate results A should be at
where A is a constant increment.
least one and preferably two or three times the half-life of the reaction. Substituting A^ and Aj into the equation above gives A
oo
- A
1
= (A
oo
- A.)e"^^l
0
(1)
A
00
A:
1
- (A
00
- A-)e
U
' 1
. .
(2)
Subtracting (2) from (1) yields
Ai - A, = (A - A^)e-'^^1(1 - e--^^
or -kA In (A| - A^) = -kt^ + In (A^ - A^)(1-e ) (3)
= -kt., + constant
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'.

Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

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Migration Tendency of Substituents in Some Cationic Rearrangement Reactions

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MIGRATION TENDENCY OF SUBSTITUENTS IN SOME CATIONIC REARRANGEMENT REACTIONS by YEN-LONG VINCENT HONG, B.S.

'V -'l 7 '

III. IV. V. VI. VII. VIII. IX. X. XI. XII.

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

R^ \ ''+ "- ^ > >.l lC

However, it raay be illustrated in sirapler systeras:

NO mechanistic study was reported.

COOEt CH dilute H,,SO, 2 4 3\

COOEt COOEt 50% H^SO, 2 4

aldehydes can be produced as well as ketones.

carbonium ion intermediate as does the pinacol rearrangement.

with either aqueous sulfuric or hydrochloric acid. product is the phenol.

methyl group, but many similar rearrangements involve intermediate

8 The proposed mechanism is shown in Scheme III:

1,2 shift AcO

Consideration of the dienone-phenol rearrangement mechanism

It is now clear, from this study

that the group

arrangement rates in acetate buffers.

in various dilute buffer solutions,

and the rearrangement is hydrogen ion catalyzed in

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

which the R group was varied.

CH/, CH/, " C

intermolecular comparisons of the rates, using compound ^ as the standard.

identify the various products.

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

conditions for migration of the group R.

However, the validity of

This system actually

charge density is high before the migration occurs.

arrangement of j6, i t i s 17, as mentioned above. to a hydroxy-substituted c a t i o n i c center i t i s 2 to 5. 28

19 methyl v. an ethyl group,

20 each rearranging system. The work described in this disertation

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

a competing methoxy fragmentation reaction occurs instead.

and unexpected, and are summarized in Table I.

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

R e l a t i v e Rate R = Ph 26 R = COOEt 14 10,000 25 0.001

35 The SeO^ method gives diselenide by-products.

can be removed from the dienones by recrystallizing from CCl^, but 24

= C^H^, 5b Scheme VII

fied from t h e synthesis of related compounds by Pleininger.

total synthesis of this compound is outlined in Scheme V I I I .

4-Methyl-4-methoxy- and 4-ethyl-4-methoxycyclohexa-2,5-dienones (7a and 7 b ) w e r e synthesized by t h e method of McKillop, 37 although

0 11 R = CH3, 7a = C^H^, Tb^

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

The procedure for

CH OCH COOEt C00Et^^3 H CHO ^COOEt

Piperidine acetate 0 15 Scheme IX

no further purification is necessary. literature 23

shows that attempted purification of ^ Both ^ and ^

extensive decomposition to o^-xylene. about 1:1 mixtures of stereoisomers.

Further separations of these

R = CH3, _5a = C^H^, 5b

R = CH3, aa = C^H^, _8b

reducing agents were investigated and all failed to give ^

chloride hexahydrate (in ethanol) reduction alla

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

were synthesized by following the pro-

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

30 42 Rickey Gross and are outlined in Scheme X.

hydration was unexpectedly difficult, but could be carried out with