I. Mechanisms of Aryl Epoxide Hydrolysis
II. Biphasic Peroxyacid Epoxidation
By
Chumang Zhao
Dissertation Submitted to the Faculty of the Graduate School
of the University of Maryland, Baltimore County
in partial fulfillment of the requirements for
the degree of Doctor of Philosophy
2007
Abstract
Many environmental pollutants such as trichloroethene, styrene, benzo[a]pyrene,
and cyclopenta[cd]pyrene are metabolized into epoxides in mammals. These epoxides are
electron-deficient species, and they alkylate DNA. If DNA is not properly repaired,
mutations leading to cancer may result. Therefore efforts to elucidate the mechanisms of
epoxide reactions are very important. Epoxides are also important synthetic precursors of
many organic compounds. A study of structure-reactivity relationships of epoxide
reactions will lead to a better understanding of the mechanisms of epoxide reactions.
5-Methoxyacenaphthylene 1,2-oxide (47) was synthesized and its hydrolysis
reactions were studied as a model for the hydrolysis reactions of cyclopenta[cd]pyrene
3,4-oxide (25). Acid-catalyzed hydrolysis of 47 yielded 64% of cis diol product, 37% of
trans diol product, and <1% of ketone. The pH-independent reaction of 47 yielded >94%
ketone. The cis and trans diols, treated with 0.1 M HClO4, underwent equilibration to
form a mixture containing 81% of trans diol and 19% of cis diol. The fact that the less
stable cis diol is the major product from acid-catalyzed hydrolysis is attributed to
transition state effects. Favorable hydrogen bonding between the carbocation
intermediate and attacking water molecule may lower the energy of the transition state
leading to the less stable cis diol.
7-Methoxynaphthalene 1,2-oxide (61), 7-methoxy-1-deuterionaphthalene 1,2-oxide
(61-1d) and 6-methoxynaphthalene 1,2-oxide (68) were synthesized, and their hydrolysis
reactions to form phenols were studied. The kinetic deuterium isotope effect in the
acid-catalyzed hydrolysis of 61 (kH(61)/ kH(61-1d) was found to be slightly inverse (0.96
± 0.01). The kinetic deuterium isotope effect on pH-independent reaction of 61 was
- ii -
found to be normal (k0(61)/k0(61-1d) = 1.09 ± 0.01). The rate of the acid-catalyzed
hydrolysis of 7-methoxy-substituted naphthalene oxide 61 was found to be only 20 times
faster than that of the unsubstituted naphthalene 1,2-oxide (75). However, 61 is 1400 time
more reactive than 75 in the pH-independent reaction. The fact that strong
electron-donating methoxy group has a relatively small substituent effect on the
acid-catalyzed hydrolysis of naphthalene oxide, but a fairly large substituent effect on its
pH-independent reaction is rationalized by mechanisms involving an “early” transition
state in the acid-catalyzed reaction and a “late” transition state in the pH-independent
reacton.
In a third investigation, we studied the epoxidation of several olefins with MCPBA
in basic biphasic conditions. We found that the epoxidation of cis-stillbene,
cis-β-methylstyrene, cis-β-deuteriostyrene, cis-2-hexen-1-ol and cis-3-hexen-1-ol results
in the formation of both cis and trans epoxides in varying ratios that depend on the
conditions. Our results are consistent with two competing mechanisms for biphasic
epoxidation, a concerted mechanism leading to only cis epoxide and a stepwise
mechanism, involving an intermediate, leading to mostly trans epoxides.
- iii -
APPROVAL SHEET
Title of Thesis:
I. Mechanisms of Aryl Epoxide Hydrolysis
II. Biphasic Peroxyacid Epoxidation
Name of Candidate:
Chumang Zhao
Thesis and Abstract Approved: __________________________Date: ____________
Dale L. Whalen
Professor of Chemistry
Department of Chemistry and Biochemistry
- iv -
CURRICULUM VITAE
Chumang Zhao
916 Hooper Ave. Apt.C
Baltimore, MD, 21229
410-536-0769
email: chumang1@umbc.edu
EDUCATION:
Ph. D. Organic Chemistry
University of Maryland, Baltimore County, September 2007
Thesis: I. Mechanisms of Aryl Epoxide Hydrolysis
II. Biphasic Peroxyacid Epoxidation
B. S. Chemistry
Zhejiang University, Hangzhou, China, July 2001
EXPERIENCE:
2001-2003 Teaching Assistant, University of Maryland, Baltimore County
2003-2007 Research Assistant, University of Maryland, Baltimore County
RESEARCH INTERESTS:
Synthetic Organic Chemistry, Mechanistic Organic Chemistry, Toxicology of
Small Molecules
PUBLICATION:
Zhao, C.; Whalen, D. L. 'Transition State Effects in the Acid-Catalyzed
Hydrolysis of 5-Methoxyacenaphthalene 1,2-Oxide: Implications for the
Mechanism of Acid-Catalyzed Hydrolysis of Cyclopenta[cd]pyrene 3,4-Oxide,'
Chem. Res. Toxicol. 2006, 19, 217-222.
-v-
Acknowledgement
I would like to express my great gratitude to my advisor, friend, and mentor, Dr.
Dale Whalen. It is Dr. Whalen who trained me to be a real chemist from a rookie hand in
chemistry lab. I have learned a lot from the continuous talk about our research,
knowledge in chemistry and his precious experience about work, life and family here in
this very different country. Without his support, patience and encouragement during my
graduate studies, my six years here in UMBC could not be so exciting and valuable.
My thanks also go to the members of my major committee, Dr. Hosmane, Dr.
Smith, Dr. Pollack, and Dr. Creighton for their steady help on my candidacy proposal and
independent proposal. With many of their inspiring comments, I was able to complete my
research that is summarized in this dissertation.
Friendship from my graduate student colleagues and postdoc, Ning, Penny,
Hongyi, Ravi, Honggang and Jules are also much appreciated and has led to many
interesting and good-spirited discussions relating to this research.
Last, but not least, I would like to thank my wife Kexin for her understanding and
love during the past few years. Her support and encouragement was in the end what made
this dissertation possible.
Thanks for those who care about me and whom I care about.
- vi -
List of Abbreviation
AIBN
2,2'-Azobisisobutyronitrile
CHES
2-[N-Cyclohexylamino]ethane-sulfonic Acid
DMSO
Dimethylsulfoxide
DNA
Deoxyribonucleic acid
EPPS
N-(2-Hydroxyenthyl)piperazine-N’-3-propanesulfonic Acid
Eq.
Equation
eq.
Equivalent
h
Hour
HPLC
High Pressure Liquid Chromatography
IR
Infrared
mp.
Melting Point
Mass Spec
Mass Spectrometry
MCPBA
m-Chloroperoxybenzoic Acid
MES
2[N-Morpholino]ethanesulfonic Acid
min
Minute
MOPSO
3-[N-Morpholino]-2-hydroxypropanesulfonic Acid
NMR
Nuclear Magnetic Resonance
MW
Molecular Weight
PAH
Polycyclic Aromatic Hydrocarbon
THF
Tetrahydrofuran
TLC
Thin Layer Chromatography
UV
Ultraviolet
- vii -
LIST OF SCHEMES, FIGURES AND TABLES
Schemes, Figures and Tables:
Page
Chapter I:
Figure 1………………………………………………………………………………2
Scheme 1……………………………………………………………………………..4
Scheme 2……………………………………………………………………………..4
Scheme 3……………………………………………………………………………..6
Scheme 4……………………………………………………………………………..7
Figure 2……………………………………………………………………………….8
Table 1………………………………………………………………………………..9
Scheme 5…………………………………………………………………………….10
Figure 3……………………………………………………………………………...11
Scheme 6…………………………………………………………………………….12
Scheme 7…………………………………………………………………………….13
Figure 4……………………………………………………………………………...14
Scheme 8…………………………………………………………………………….15
Scheme 9…………………………………………………………………………….16
Scheme 10…………………………………………………………………………...17
Scheme 11…………………………………………………………………………...18
Chapter II
Scheme 12…………………………………………………………………………...23
- viii -
Figure 5…………………………………………………………………………...…25
Table 2………………………………………………………………………………26
Figure 6……………………………………………………………………………...28
Table 3………………………………………………………………………………28
Table 4………………………………………………………………………………31
Scheme 13…………………………………………………………………………...33
Figure 7…………………………………………………………………………...…34
Chapter III
Scheme 14…………………………………………………………………………...54
Scheme 15…………………………………………………………………………...55
Scheme 16…………………………………………………………………………...56
Table 5………………………………………………………………………………57
Table 6………………………………………………………………………………58
Figure 7……………………………………………………………………………...58
Table 7………………………………………………………………………………59
Table 8………………………………………………………………………………60
Table 9………………………………………………………………………………60
Table 10……………………………………………………………………………..61
Table 11……………………………………………………………………………..62
Table 12……………………………………………………………………………..63
Figure 9……………………………………………………………………………...63
Table 13……………………………………………………………………………..66
- ix -
Figure 10…………………………………………………………………………….67
Table 14…………………………………………………………………………….68
Table 15……………………………………………………………………………..68
Figure 11…………………………………………………………………………….69
Table 16……………………………………………………………………………..72
Figure 12…………………………………………………………………………….72
Scheme 17…………………………………………………………………………...74
Scheme 18…………………………………………………………………………...75
Scheme 19…………………………………………………………………………...75
Scheme 20…………………………………………………………………………...77
Scheme 21…………………………………………………………………………...78
Scheme 22…………………………………………………………………………...78
Scheme 23…………………………………………………………………………...81
Chapter IV
Scheme 24………………………………………………………………………….111
Scheme 25………………………………………………………………………….114
Scheme 26………………………………………………………………………….117
Scheme 27………………………………………………………………………….118
Table 17……………………………………………………………………………120
Table 18……………………………………………………………………………121
Table 19……………………………………………………………………………121
Scheme 28………………………………………………………………………….123
-x-
Scheme 29………………………………………………………………………….123
Scheme 30……………………………………………………………….................124
Scheme 31………………………………………………………………………….125
Scheme 32………………………………………………………………………….126
Scheme 33………………………………………………………………………….126
- xi -
TALBLE OF CONTENTS
CONTENTS
PAGE
Title Page..………………………………………………………………………..…..…....i
Abstract………………………………………………………………………………...….ii
Approval Sheet………………………………………………………………...………. ..iv
Curriculum Vitae…………………………………………..……………………...............v
Acknowledgement……………………………………………………………...………. .vi
List of Abbreviation…………………………………………………………….…..…....vii
List of Figures and Tables…………………………………………………....... ……....viii
Table of Content………………………………………………………………..………..xii
- xii -
I. Introduction…………………………………………………………………………1
A. Naturally Occurring Epoxides………………………………………………2
B. Epoxides as Intermediates in the Metabolism of Polycyclic Aromatic
Hydrocarbons (PAH’s)………………………………………………………..3
1. Benzo[a]pyrene………………………………………………………………..3
2. Naphthalene………………………..………………………………………….5
3. Cyclopenta[cd]pyrene…………………………………………………………6
C. Mechanisms of Hydrolysis of Epoxides…………………………………...6
1. Mechanisms of Hydrolysis of Simple Alkyl Epoxides………………………..6
2. Mechanisms of Acid-catalyzed Hydrolysis of Vinyl-substituted Epoxides…..8
3. Mechanisms of Hydrolysis of Aryl-substituted Epoxides………………………..10
a. Hydrolysis of Substituted Styrene Oxides……………………………….10
b. Hydrolysis Reactions of Naphthylene 1,2-Oxide…………………..…...13
4. Hydrolysis Reactions of Cyclopenta-fused Arene Oxides…………………...14
a. Hydrolysis of 5-Methoxyindene 1,2-Oxide ……………………………..14
b.
Hydrolysis of Acenaphthylene Oxide and Cyclopenta[cd]pyrene
3,4-Oxide………………………………………………………………...17
D. Research Objectives………………………………………………………………20
1. Hydrolysis of 5-Methoxyacenaphthylene 1,2-oxide: A Model for the Reaction
of Cyclopenta[cd]pyrene 3,4-Oxide………………………………………….20
- xiii -
2. Synthesis and Hydrolysis Reactions of 6-Methoxynaphthalene 1,2-Oxide,
7-Methoxynaphthalene 1,2-Oxide and 7-Methoxy-1-deuterionaphthalene
1,2-Oxide: A Study of Arene Oxide-Phenol Rearrangement………………..20
3. Non-stereospecific Biphasic Epoxidation……………………………………21
II. Hydrolysis Reactions of 5-Methoxyacenapthylene 1,2-Oxide (47)…..22
A. Synthesis of 5-Methoxyacenaphylene 1,2-oxide (47), cis Diol 49,
trans Diol 50 and Ketone 48………………………………………………23
B. Results………………………………………………………………………….25
1. Procedure for Monitoring Rates of Reaction of 5-Methoxyacenaphthylene
1,2-Oxide …………………………………………………………………..25
2. Product Studies of the Hydrolysis of 5-Methoxyacenaphthylene 1,2-Oxide...26
a. Acid-Catalyzed Reaction………………………………………………...26
b. pH-Independent Reaction...………………………………………………….27
3. Acid-Catalyzed Equilibration of Cis and Trans Diol 49 and 50……………..27
C. Discussion……………………………………………………………………...30
1. Reactivities of 5-Methoxyacenaphthylene 1,2-Oxide (47) in Acid-catalyzed
and pH-Independent Reactions……………………………………………..30
a. Acid-Catalyzed of 47 …………………………………………………...30
b. pH-Independent Reaction of 47 ………………………………………...32
- xiv -
2. Comparison of cis/trans Diol Product Ratio from Acid-Catalyzed Hydrolysis
of 47 and Equilibrium cis/trans Diol Ratio for 49 and 50……………………32
D. Conclusions……………………………………………………………………36
E. Experimental…………………………………………………………………..37
1. Material and Methods………………………………………………………..37
2. Synthesis……………………………………………………………………..37
III. Hydrolysis of Hydrolysis of 7-Methoxynaphthalene 1,2-oxide (61),
7-Methoxy-1-deuterionaphthalene 1,2-Oxides (61-1d) and
6-Methoxynaphthalene 1,2-Oxide (68) ……………...................................53
A. Results………………………………………………………………………….54
1. Synthesis of Naphthalene Oxides 61, 61-1d, 68 and 75……………………..54
2. Kinetic Studies of Substituted Naphthalene Oxides 61 and 68……………...56
3. Solvent Effect on the Hydrolysis Reactions of Epoxide 61………………….59
4. Isotope Effects on the Hydrolysis Reactions of
7-Methoxy-1-deuterio-naphthalene 1,2-Oxides (61-1d)…………………….62
a. Rate-pH Profiles of 61-1d ………………………………………………62
b.Kinetic Isotope Effects on the Hydrolysis Reactions of 61……………...64
5. Substituent Effects on the Hydrolysis of Naphthalene 1,2-Oxide (75)……...66.
6. Solvent Isotope Effects on the Hydrolysis Reactions of 61 …………………67
7. Product Studies of the Hydrolysis Reaction of 61 and 68…………………...69
- xv -
a. HPLC Product Studies ………………………………………………….69
b. Semi-preparative Reactions: 1H NMR Identification of the Hydrolysis
Products of 61, 61-1d and 68…………………………………………..70
B. Discussion…………………………………………………………… ………..73
1. Mechanisms of the Acid-catalyzed Hydrolysis of 61………………………..73
a. Substituent Effects on Acid-catalyzed Hydrolysis of 61………………..73
b. Kinetic Deuterium Isotope Effects on the Acid-catalyzed Hydrolysis of
61-1d………………………………………………………………………74
2. Mechanisms of the pH-Independent Reaction of 61…………………………76
a. Substituent Effects of pH-Independent Reaction of 61………………….76
b. Kinetic Deuterium Isotope Effects on the pH-Independent Reaction of
61-1d……………………………………………………………………76
3. Solvent Isotope Effect on the Hydrolysis Reaction of 61……………………79
4. Solvent Effect on the Acid-catalyzed and pH-Independent Reaction of 61…80
5. Product Study of the Acid-catalyzed and pH-Independent Reaction of
61-1d................................................................................................................81
C. Conclusion……………………………………………………………..............83
D. Experimental…………………………………………………………………..84
1. Materials and Methods……………………………………………………….84
2. Synthesis……………………………………………………………………..84
- xvi -
IV. Biphasic Epoxidation Mechanisms……………………………………….110
A. Introduction to Mechanisms of Epoxidation by Peroxyacids……….111
B. Results………………………………………………………………………...114
1. Observations from Biphasic Epoxidation of cis-Stilbene…………………..113
2. Special Biphasic Epoxidation Procedure…………………………………...115
3. Factors in Determining Yields of trans Epoxides from cis Olefins…...……116
C. Discussion……………………………………………………………………121.
1. Possible Mechanisms……………………………………………………….122
2. Nature of the Epoxidizing Reagent…………………………………………127
D. Experimental…………………………………………………………………129
1. Purification of MCPBA…………………………………………………….129
2. Synthesis……………………………………………………………………129
V. References………………………………………………………………………..135
- xvii -
Chapter I
Introduction
-1-
A. Naturally Occurring Epoxides
The epoxide functional group is a three-membered heterocycle containing an
oxygen atom, with estimated strain energy of 27 kcal/mol.1 Epoxides undergo ring
opening easily in their reactions with acidic and nucleophilic reagents to release this
strain energy. This special feature allows epoxides to play important roles in many
essential biological processes. The epoxide group is found in many naturally occurring
compounds, and they are also important intermediates in the syntheses of complicated
organic compounds.
Numerous natural products or xenobiotics contain the epoxide functional group
within their chemical structures. For example, the epoxide functional group is present in
guaianolide derivatives. These compounds are from Artemisia myriantha and used for the
treatment of menorrhagia and inflammatory diseases.2 The epoxide functional group is
also present in calafianin, isolated from the sponge Aplysina gerardogreeni, a Mexican
marine organism, and also in the thiol protease inhibitor named E-64, isolated from a
solid culture of Aspergillus japonicus TPR-64.3-5 (Figure 1)
O
H
O
O
H
H
O
Br
NH2
O
H
N
O
N
N
H
O
N
O
O
Br
H2N
H
Calafianin
Figure 1. Naturally occurring epoxides
-2-
O
H
O
O
Guaianolide Derivatives
N
H
O
H
N
E-64
N
H
OH
O
O
Epoxides are also used as important intermediates in organic synthesis. For
example, epoxidation is one of the most important steps in the synthesis of merrilactone
A, a natural product with potential implications for the treatment of neurodegenerative
diseases.6 Epoxide-initiated electrophilic cyclization of azides is also employed in
preparing the azabicyclic ring skeleton,7 an important structural subunit present in
Arthropod Alkaloids.8 Asymmetric epoxidations of olefins are still being reported for the
syntheses of enantiomerically enriched epoxides.9
B. Epoxides as Intermediates in the Metabolism of Polycyclic Aromatic
Hydrocarbons (PAH’s)
1. Benzo[a]pyrene
The reactions of epoxides in biological systems have been extensively studied, as
the human body itself produces epoxides in the metabolism of many unsaturated
hydrocarbons. For example, when benzo[a]pyrene (BaP) is absorbed into the human
body (Scheme 1), it is oxidized in a reaction catalyzed by cytochrome P450, a
well-known phase I enzyme, to an arene oxide. The arene oxide is then hydrolyzed in a
reaction catalyzed by epoxide hydrolase to a dihydrodiol of BaP, which is further
oxidized
to
give
7,8-Dihydroxy-9,
two
isomeric
diol
epoxides.
One
of
10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene
these
epoxides,
(DE-2),
was
proposed to be the ultimate metabolite responsible for the carcinogenic and mutangenic
properties of BaP.10-12
-3-
Scheme 1. Metablism of Benzo[a]pyrene (BAP)
11
1
12
2
10
7
6
H2O
O2
4
8
Epoxide Hydrolase
P450
3
9
HO
OH
O
5
50
P4
Arene Oxide
Benzo(a)pyrene
d
Hy
de
oxi
p
E
Dihydrodiol
ase
rol
O
O
HO
HO
OH
OH
(-) - syn-Diol Epoxide of BaP (DE-1)
(+) - anti-Diol Epoxide of BaP (DE-2)
HIGHLY CARCINOGENIC
DNA
DNA/H2O
O
HO
OH
HO
HO
HO
OH
HO
OH
(-) - syn-Diol Epoxide of BaP (DE-1)
OH
~5% DNA-adduct
95% Tetrols
Mostly Cis Adduct
O
DNA
DNA/H2O
OH
HO
HO
HO
HO
OH
(+) - anti-Diol Epoxide of BaP (DE-2)
HO
OH
~10% DNA-adduct
OH
90% Tetrols
Mostly Trans Adduct and Mostly Trans Diol
Scheme 2. Reactions of diol epoxide with DNA/H2O
-4-
The epoxy metabolites of BAP are electrophilic species that are able to alkylate
the base residues in DNA to give covalent adducts (shown in Scheme 2).13 It is known
from structural studies that the primary alkylation sites of DNA are the exocyclic amino
groups in purine bases.9 These modifications may cause mutations and disrupt normal
biological processes, leading to cancer.10
2. Naphthalene
Naphthalene, isolated from coal tar and a primary ingredient in mothballs, is a
hydrocarbon with two fused benzene rings. It has been widely used in antiseptics and
insecticides.14 Naphthalene is a volatile, white solid. Animal studies have shown that
female mice exposed to naphthalene vapor develop lung cancer. Based on this evidence,
the Department of Health and Humans Services (DHHS) concluded that naphthalene is
reasonably anticipated to be a human carcinogen.15-17
Naphthalene is metabolized in the human body by a series of reactions catalyzed
by P450 oxygenases and epoxide hydroxylase. Naphthalene 1,2-oxide was identified as
an intermediate in the microsomal hydroxylation of naphthalene.18 This epoxide
undergoes isomerization at biological pH to give 1-naphthol.18 The biological toxicities
of naphthalene may be due to the alkylation of biomolecules by naphthalene 1,2-oxide, or
to the reactions of naphthoquinone, a metabolites of naphthol, with biomolecules.19 Many
details about the pathways of metabolism of naphthalene are still uncertain.
-5-
3. Cyclopenta[cd]pyrene
Cyclopenta[cd]pyrene (CPP), a ubiquitous environmental pollutant, is a
cyclopenta-fused PAH with potent tumoricity. Cyclopenta[cd]pyrene 3-4-oxide (CPPO)
has been proposed to be the ultimate metabolite responsible for its carcinogenicity. 20
Biological activation of CPP yields CPPO, which reacts with DNA to yield
mostly cis adducts along with some trans isomer (Scheme 3),21 and it was reported that
CPPO forms DNA adducts almost exclusively with deoxyguanosine.22
Scheme 3. Biochemical Reaction of CPP
H
O
HO
1) DNA
Activation
N
N
O
HO
N
N
NH
N
N
O
HO
HO
OH
OH
cis Adduct (major)
CPPO
H
N
N
NH
2) Enzymic
Degradation
CPP
O
O
trans Adduct (minor)
C. Mechanisms of Hydrolysis of Epoxides
1. Mechanisms of Hydrolysis of Simple Alkyl Epoxides
The epoxide functional group undergoes ring opening reaction with acidic and
nucleophilic reagents to release the strain energy.1 However, when epoxides undergo
reactions, the mechanism of epoxide ring opening varies with the epoxide structures.
In acid solution, an epoxide acts as a basic site for protonation. The protonated
epoxide undergoes ring opening to give a β-hydroxy carbocation if the positive charge is
-6-
stabilized sufficiently by adjacent functional groups such as tertiary carbon, vinyl,
H
O
O
R1
R3
1)
R2
HA
R4
R1
R3
R2
R4
H
O
2)
R1
R2
HA
R4
OH
R2
R3
R4
A
O
R3
R1
R1
R3
R2
R4
- H+
HO
R1
R2
R1
H2O
- H+
OH
R2
OH
R4
R3
R3
R4
OH
H2O
O
3)
O
R1
R3
R2
R4
R1
R2
H+
R3
R4
HO
R1
R2
OH
R3
R4
OH
OH(or H2O)
Scheme 4. General mechanisms of hydrolysis of oxide
or phenyl (Scheme 4-1). In this mechanism, a solvent molecule can attack from either
side of the electron-deficient carbon. If there are no such adjacent functional groups,
alternative mechanisms involve water attack on the protonated epoxide or water attack
concerted with proton transfer (Scheme 4-2). In neutral or basic solution, water or
hydroxide ion attacks the expoxide ring (Scheme 4-3). Proton transfer from solvent to the
epoxide oxygen may be concerted with water attack. In this mechanism, nucleophilic
attack from the back side of the epoxide carbon results in 100% inversion of carbon
configuration.
The mechanism of reaction of an epoxide in aqueous solution varies with the pH
value of the solution. A typical rate expression for the reaction of epoxides is described in
Eq. 1, where kH is the specific second-order rate constant for the hydronium ion-catalyzed
reaction, k0 is the specific first-order rate constant for a pH-independent reaction, and kOH
is the specific second-order rate constant for the hydroxide-catalyzed reaction.
-7-
kobsd = kH[H+] + ko + kOH[OH-].................................................... Eq. 1
Shown in Figure 2 is the rate-pH profile of hydrolysis of isobutylene oxide. From
this typical rate-pH profile, it can be concluded that there are three kinetically
distinguishable
mechanisms.
In
acid
solution, where kH[H+] >> ko + kOH[OH-],
the hydrolysis of isobutylene oxide is
catalyzed
by
hydronium
protonated
epoxide
undergoes
ring
ion.
functional
opening
to
The
group
form
Figure 2. Caculated pH-rate profile for
a
hydrolysis of isobutylene oxide24
carbocation, which reacts with water to
form a glycol. In the neutral pH range, where ko >> kH[H+] + kOH[OH-], or when the pH is
over 12, where kOH[OH-] >> kH[H+] + ko, the epoxide undergoes nucleophilic attack by
either water (k0) or hydroxide ion (kOH), respectively, to give the glycol product.23, 24
2. Mechanisms of Acid-catalyzed Hydrolysis of Vinyl-substituted Epoxides
Stereochemical studies showed that in the acid-catalyzed hydrolysis of an epoxide
containing only primary or secondary carbons, only products from inversion of
configuration at carbon are formed.25 In another words, the resulting carbocation is not
sufficiently stabilized to exist as an intermediate. While in systems with tertiary carbons
or vinyl groups, the positive charge can be stabilized, resulting in much faster rates in
acid-catalyzed hydrolysis. The bimolecular rate constant for acid-catalyzed hydrolysis of
-8-
ethylene oxide is only 9×10-3 M-1s-1.23
The biomolecular rate constants of the
acid-catalyzed hydrolysis of isobutene oxide 1, butadiene oxide 2, cyclopentadiene oxide
3 and cyclohexadiene 4 are shown in Table 1.
Table 1. Bimolecular rate constants for hydronium ion-catalyzed hdyrolysis of a
series of epoxides in water, 25 °C
Epoxides
kH (M-1s-1)
Epoxides
O
O
6.8 a
1.7 b
2
1
O
O
3.7 × 103 b
1.1 × 104 b
3
a
kH (M-1s-1)
4
Taken from Ref. 23. bTaken from Refs. 26, 27, 28.
A product study showed that the acid-catalyzed hydrolysis of 2 yields only 4% of
1,4-diol product and 96% of 1,2-diol product, which clearly showed that the resulting
carbocation is not fully developed. The main pathway of this reaction is most likely the
attack of water on the protonated epoxide.
The ability of a vinyl group to stabilize a carbocation increases dramatically if the
vinyl group is in a ring structure.29 The acid-catalyzed hydrolysis of cyclopentadiene
oxide and cyclohexadiene oxide give both 1,2 and 1,4 diols.26-28 It is thought that the
reactions proceed via carbocation intermediates.29
-9-
3. Mechanisms of Hydrolysis of Aryl-Substituted Epoxides
a. Hydrolysis of Substituted Styrene Oxides
The acid-catalyzed hydrolysis reactions of substituted styrene oxides give mostly
glycol products, and their rates also fit Eq.1. The rates of acid-catalyzed hydrolysis and
methanolysis of substituted styrene oxides give good Hammett correlations, with a ρ+
value of -4.2 for hydrolysis30 and a ρ+ value of -4.1 for methanolysis,31 indicating
significant positive charge developed on the benzyl carbon at the transition state.
Product studies show that the acid-catalyzed hydrolysis of styrene oxide 5 yields
styrene glycol with 67% inversion of configuration and 33% retention of configuration at
the benzyl carbon.30
OH2
H
O
OH
H
H
OH
OH
H
H
6
5
HO
H
H
H2O
Racemic diol
OH2
7
8
Mostly inverted diol
¦Ä+
O
H
OH
H
inverted diol
¦Ä+
OH2
OH
9
10
Scheme 5. The mechanisms of acid-catalyzed hydrolysis of styrene
oxide and the corresponding configuration of diol products
This result indicates that acid-catalyzed hydrolysis of styrene oxide does not
proceed completely via a freely solvated carbocation intermediate. The lifetime of the
benzyl carbocation is not long enough for it to be symmetrically solvated by water, which
- 10 -
would yield fully racemic products. This result can be accounted by a combination of the
“borderline SN2” mechanism25 and carbocation intermediate mechanism (Scheme 5).
Water attacks exclusively on the benzylic carbon because the phenyl ring stablizes the
positive charge on the benzylic position in the transition state.
Rate-pH
profiles
acid-catalyzed
hydrolysis
of
of
a
series of para-substituted styrene
oxides show three regions: (1)
acid-catalyzed,
pH-independent,
(2)
and
(3)
Figure 3. Plots of log kobsd for hydrolysis of
para-substututad styrene oxides vs pH30
base-catalyzed hydrolysis (Figure
3). Large substituent effects are observed in the rates.28, 30
In the acid-catalyzed reaction, the rates correlate with the abilities of para
substituents to stabilize the positive charge developed at the benzyl position in the
transition state. For example, kH for para-methoxystyrene oxide is 105 times larger than
the kH of para-nitrostyrene oxide.32 In neutral conditions, the ko value also varies
significantly with the substituent. However, the kOH values for nucleophilic addition of
hydroxide ion to styrene oxides are very similar to each other, indicating that the
substituent effect on this reaction is very small.
- 11 -
It is worth noticing that in the rate-pH profile for the hydrolysis of
para-methoxystyrene oxide (11) when [OH ] < 1 M, k0 >> kOH[OH-] and there is no
base-catalyzed hydrolysis of this compound.30 Possible mechanisms for aldehyde
formation in its pH-independent reaction are a β-hydride migration concerted with ring
opening of epoxide, or a ring opening step followed by hydride migration (Scheme 6).
O
H
H
O
H3CO
12
H
H
O
O
H2O
H3CO
14
H
H3CO
11
H
H3CO
H
O
13
D
O
(H)D
H3CO
H2O
H
H3CO
H(D)
O
diol
H3CO
H
15
D
H
17
15
Scheme 6. Possible mechanisms for aldehyde 15 formation in the
hyrolysis of para-Methoxystyrene Oxides at pH 8-14
It
has
been
observed
that
the
pH-independent
reaction
of
4-methoxy-trans-β-deuteriostyrene oxide is accompanied by isomerization to its
cis-β-deuterio isomer (17) along with some diol products. The details of the mechanism
of this reaction will be discussed in further detail in later chapters.
- 12 -
b. Hydrolysis Reactions of Naphthalene 1,2-Oxide
The rate-pH profile of naphthalene 1, 2-oxide contains an acid-catalyzed region and
a pH-independent region. In either of these two pH region, hydrolysis of naphthalene
1,2-oxide yields exclusively 1-naphthol.33, 34
The mechanism of the pH-independent reaction of deuterionaphthalene oxide 18
involves intermediate 21, which aromatizes to naphthol 22 (Scheme 7).33 The
intramolecular migration of hydrogen in this reaction has been referred as the “NIH
shift”.35 Further studies showed that the NIH shift is a common phenomenon in the
D
O
H O
path a
H
OH
18
19
D (H)
path b
O
D
O
22
D(H)
H
H
21
20
Scheme 7. NIH shift of naphthalene 1,2-oxide
metabolism of PAH’s, as well as in the non-enzymatic reactions of PAH epoxides at
biological pH.36, 37
In order to establish the mechanism of aromatization of naphthalene oxide, the
deuterium labeled naphthalene 1,2-oxide-1d 18 was synthesized. The kH/kD varies for
- 13 -
both acid-catalyzed hydrolysis and pH-independent reaction were reported to be 1.05 and
1.06, respectively.33 The lack of a large primary isotope effect in the pH-independent
reaction was interpreted in terms of a stepwise mechanism (path b in Scheme 6) leading
to the ketone 21. The observation that ~80% of deuterium atoms remain in the phenol
product is attributed to an isotope effect in the aromatization of ketone 21.36, 37
4. Hydrolysis Reactions of Cyclopenta-fused Arene Oxides
Cyclpenta-fused epoxides contain a five-membered ring fused with other aryl ring
systems. Examples are 5-methoxyindene 1, 2-oxide (23), acenaphthylene oxide (24) and
cyclopenta[cd]pyrene 3,4-oxide (CPPO) 25. In this class of epoxides, the fused ring
systems (benzene, naphthalene, pyrene) are able to stabilize the positive charge
developed at the benzylic position such that in acid-catalyzed hydrolysis, the reaction
O
goes via carbocations. Each
O
O
of these epoxides undergoes
H3CO
a pH-independent reaction to
yield
mainly
a
23
24
25
Figure 4. Cyclopenta-fused epoxides
ketone
product, and the second-order reactions with hydroxide ion are not observed at [OH-] < 1
M.21, 38
a. 5-Methoxyindene 1,2-Oxide 23
The acid-catalyzed hydrolyses of 23 yields the corresponding cis and trans diols 27
and 28, with a cis/trans ratio of 80:20. It was also reported that acid-catalyzed hydrolysis
of indene 1,2-oxide yields diol products with a cis/trans ratio of 75:25.39 The similar
- 14 -
cis/trans diol ratios are consistent with a mechanism in which each epoxide reacts with
H+ to form a carbocation intermediate, and the substituent does not significantly
influence the ratio of cis vs. trans attack of solvent on the intermediate.38
OH
Scheme 8. Hydrolysis of 5-methoxyindene 1, 2-oxide
OH
H3CO
OH
OH
H+
H3CO
O
27
H2O
26
kH
OH
+
H
H3CO
H3CO
k0
28
23
O
H3CO
27
28
29
An important observation is that acid-catalyzed hydrolysis of 23 yields cis diol
product 27 as the major product (80:20 cis/trans ratio). One possible explanation for this
observation is that the cis diol is more stable than the trans diol. In order to compare the
relative stabilities of 27 and 28, the acid-catalyzed equilibration of 27 and 28 in 0.05 M
HClO4 water solution at 25 ± 0.2 °C was carried out. This study showed that at
equilibrium, the ratio of diols 27:28 is 40:60. Therefore, the cis diol 27 is the
thermodynamically less stable product.38 The fact that the less stable cis diol is the major
product from acid-catalyzed hydrolysis of 23 must be due to transition state effects that
selectively lower the energy of the transition state leading to the cis diol.
- 15 -
Quantum chemical calculation of the structure of carbocation 26 showed that its
conformation is almost planar, and water molecules are able to attack the intermediate
from either side.38 However, in the transition state for cis attack, intramolecular hydrogen
H2O
H3CO
O
H3CO
OH
26
23
H2O
H
H
H3CO
O
H3CO
OH
O
H
Cis attacking
O
H
Trans attacking
30
31
-H
-H
H3CO
H3CO
OH
OH
OH
29
27
OH
Scheme 9. Hydrolysis of substituted indene oxides
bonding between the attacking water molecule and the adjacent hydroxyl group may
lower the transition state energy barrier leading the less stable cis diol, which makes the
this transition state energetically favored. In the transition state leading to the trans diol,
there is no effective hydrogen bonding between the attacking water molecules and the
OH group because of the much longer distance between the O and H atoms (Scheme 9).38
- 16 -
It is also interesting to note that in neutral or basic solution, the hydrolysis of 23
yields ketone product 29. For example, at pH = 6-9, 23 reacts via a pH-independent
reaction to give 71% of ketone 28, and diols are minor products in a ratio of 75:25
cis/trans.
b. Acenaphthylene Oxide (24) and Cyclopenta[cd]pyrene 3,4-Oxide (25)
Acenaphthylene oxide and CPPO are very similar in structure. In the hydrolysis
of the both compounds there is only an acid-catalyzed hydrolysis and a pH-independent
reaction. CPPO, however, reacts much faster than acenaphthylene oxide due to the
greater stabilization of the carbocation intermediate by the pyrene ring system.
Scheme 10. Products from hydrolysis of acenaphthylene oxide
O
HO
OH
HO
OH
HO
O
+
H ( pH = 3.0 )
24
H+
(p
33
64%
32
H
=
10
) HO
OH
5%
OH
HO
8%
34
32%
35
4%
O
87%
Scheme 10 shows the products of hydrolysis of acenaphthylene oxide 24.
Acid-catalyzed hydrolysis of 24 yields mainly diol products along with a small amount of
ketone. Furthermore, cis diol 33 is the major product. In the pH-independent reaction,
- 17 -
ketone 35 becomes the major product (87%).21 The cis/trans diol ratio in the
acid-catalyzed hydrolysis of CPPO (25, Scheme 11) is similar to that from the
acid-catalyzed hydrolysis of 24. The pH-independent reaction of 25, however, yields
almost exclusively ketone, reflecting a stronger tendency of hydride migration.
Scheme 11. Product distribution of hyrolysis of CPPO
4
OH
HO
OH
O
3
H2O
H+ (pH=1.8)
25
HO
HO
O
H+
(pH
36
=7
.0)
37
O
60%
38
34%
39
< 6%
> 98%
The acid-catalyzed hydrolyses of 24 and 25 yield similar ratios of cis and trans
diols, indicating that the cyclopenta-fused ring of carbocations 32 and 36 have very
similar structural features. It is noticed that the cis diol yield is almost twice as much as
the trans diol yield, which is unusual because water can attack the intermediate on both
sides. It is calculated that in 25, positive charge is better stabilized on carbon 3 than on
carbon 4.40 In 24, C-1 and C-2 carbons are chemically identical to each other.
In the reactions of some epoxides, 1-(4-methoxyphenyl)cyclohexene-1,2-oxide,
for example, the cis diol is the major product, and it is also more stable than the
- 18 -
corresponding trans diol.41 In this case, the structural features present in the more stable
cis diol product may also contribute to lowering the transition state energy for cis diol
formation.41 Treatment of cis and trans diols 37 and 38 in 0.1 M HClO4 leads to
decomposition, and equilibration was not observed.42
- 19 -
E. Research Objectives
1. Hydrolysis of 5-Methoxyacenaphthylene 1,2-Oxide: A Model for the Reactions of
CPPO
Our goal for this study is to synthesize 5-methoxyacenaphthylene 1,2-oxide and
determine its rate-pH profile. If the rate-pH profile and product distributions are
comparable to that of the CPPO, we will attempt the equilibration of the corresponding
cis and trans diols to determine their relative stabilities. Since the cyclopenta-fused ring
system of 5-methoxyacenaphthylene 1,2-oxide and cyclopenta[cd]pyrene 3,4-oxide have
very similar geometries, the relative stabilities of the corresponding cis and tran diols
should also be very similar. This study will provide a better understanding of why
cyclopenta[cd]pyrene 3,4-oxide reacts with DNA and also with acidic water solution to
yield mainly cis products.
2. Synthesis and Hydrolysis Reactions of 6-Methoxynaphthalene 1,2-Oxide and
7-Methoxynaphthalene 1,2-Oxide and 7-Methoxy-1-deuterionaphthalene 1,2-Oxide:
A Study of an Arene Oxide-Phenol Rearrangement
Rate-pH profiles and products of the reaction of 6- and 7-methoxynaphthalene
1,2-oxides will be determined and compared to published results for the hydrolysis
reactions of naphthalene 1,2-oxide. The effect of the methoxy groups, which greatly
stabilize the carbocation intermediates formed in the acid-catalyzed reaction, will be
evaluated. We hope to be able to detect cis and trans diols formed in their acid-catalyzed
reactions to determine if transition state effects favor cis diol formation.
- 20 -
1-Deuterio-7-methoxynaphthalene 1,2-oxide will be synthesized and its rearrangement to
phenol via a “NIH” shift mechanism will be studied.
3. Non-stereospecific Biphasic Epoxidation
The mechanisms for perxoyacid epoxidation of olefins by peroxyacids have been
intensively studied. Calculational and experimental results suggest either the butterfly
mechanism proposed by Bartlett43 or the asynchronous mechanism proposed by
Hanzlik.44 In ether of these mechanisms, the reaction is thought to be concerted and
stereospecific. An oxygen atom is inserted into the carbon-carbon double bond in one
step.
But here in our lab, we have observed that epoxidations of a series of cis olefins
by MCPBA in biphasic conditions also yield trans epoxides, possibly by a two-step
mechanism. We will explore the epoxidation of various cis olefins to determine if the
structure of olefins play a role in the non-stereospecific reactions.
- 21 -
Chapter II
Hydrolysis Reactions of 5-Methoxyacenapthylene
1,2-Oxide
- 22 -
A. Synthesis of 5-Methoxyacenaphylene 1,2-Oxide 47, cis Diol 49, trans
Diol 50 and Ketone 48
The synthesis of 47-50 from 1,2-dihydroacenaphthlene 40 was accomplished by
the
synthetic
route
outlined
in
5-nitro-1,2-dihydroacenaphthylene
Scheme
41,45
12.
Nitration
which
of
was
40
yielded
converted
to
5-amino-1,2-dihydroacenaphthylene 41 by catalytic hydrogenation.46 High-temperature
hydrolysis of 5-amino-1,2-dihydroacenaphthylene 42 with aqueous sulfuric acid yielded
5-hydroxy-1,2-dihydroacenaphthylene
43,47
which
was
converted
to
5-methoxy-1,2-dihydroacenaphthylene 45 by methylation of 44 with dimethyl sulfate.48,
49
Reaction of 5-Methoxy-1,2-dihydroacenaphthylene 45 with dicyanodichloroquinone
(DDQ) yielded the epoxide precursor 5-methoxyacenapthylene 46,50,
converted
into
5-methoxyacenapthylene
1,2-oxide
47
by
51
which was
epoxidation
with
dimethydioxirane.52-55 The reaction of 46 with osmium tetraoxide, followed by reduction
of the osmate ester with sodium bisulfite afforded cis-diol 49. Trans-diol 50 was prepared
by reaction of the olefin with iodine and silver benzoate followed by hydrolysis of the
dibenzoate product in basic methanol. Ketone 48 was prepared by hydrolysis of 47 at pH
7.05. The structure of 48 was confirmed by 1H NMR and NOE spectra.
- 23 -
i
ii
iii
NH2
NO2 41
40
OH
42
43
iv
O
OCH3
47
OCH3 46
OCH3 45
48
44
xii
viii
OCH3
OK
xi
ix
O
v
vi
vii
x
HO
HO
OH
OH
OCH3
OCH3
49
50
Reagents and Conditions: (i) 70% HNO3/Acetic acid, (ii) H2, Pd/C, Ethanol, (iii) 10%
H2SO4, 200 °C, 4 hours, (iv) KOH (v) Dimethylsulfate (vi) DDQ/Benzene, (vii)
Dimethyldioxirane in acetone, (viii) pH ≈ 7.8, (ix) OsO4, (x) NaHSO3 (aq.), (xi) Iodine,
silver benzoate, (xii) KOH, aqueous methanol
Scheme 12. Synthesis of 5-methoxyacenapthylene 1,2-oxide (47), cis-diol 49, tran-diol 50,
and ketone 51
- 24 -
B. Results
1. Procedure for Monitoring Rates of Reaction of 5-Methoxyacenaphthylene
1,2-Oxide (47)
The synthesis of 47 was accomplished by the reaction of dimethyldioxirane with
46 in acetone. This epoxide is too reactive in water or dioxane/water solutions containing
mostly water for its rates to be determined by a simple mixing technique. In 50:50
dioxane/water solutions, however, the rate of the pH-independent reaction of 47 is
sufficiently slow to be conveniently measured (half-life 22 s). Its pH rate profile over the
pH range 4-8 is given in Figure 5.
For each kinetic run,
0.0
a stock solution of 47 in
dioxane (1 mg/mL) was
log kobsd, s
-1
approximately 10-15 µL of
-0.5
-1.0
-1.5
added to 2.0 mL of 50:50
-2.0
4
5
6
7
8
pH
dioxane/water solution in
Figure 5 Plot of log kobsd for reaction of 47 vs apparent pH,
the
thermostated
cell
50:50 dioxane/water, 0.1 M NaClO4, 25.0 ¡À0.2 oC.
compartment (25.0 ± 0.2 ℃) of a UV-vis spectrophotometer. Reactions were monitored
at 265 nm, and pseudo-first-order rate constants were calculated by nonlinear regression
analysis of the absorbance vs time data. The results are summarized in Table 2.
- 25 -
Table 2. Observed rate constants as a function of pH for hydrolysis of 47 in 50:50
dioxane/water in 0.1 M NaClO4, 25 ± 0.2 °C
Buffer, 0.002 M
EPPS
HEPS
MES
MES
No Buffer
No Buffer
No Buffer
No Buffer
kobsd × 102, s-1
3.5630
3.4430
3.3640
3.5020
4.1510
4.6710
6.1310
11.410
pH
8.01
7.01-7.03
6.08
5.44-5.47
5.06
4.74-4.77
4.58-4.60
4.17 – 4.20
% Error
0.72
0.42
0.53
0.46
0.73
0.42
0.80
0.89
In this solvent, acid-catalyzed hydrolysis occurs at pH < ~5, and a pH-independent
reaction occurs at pH > ~5. Rate data were fit to the equation kobsd = kH[H+] + ko, where
kH is the second-order rate constant for acid-catalyzed hydrolysis and ko is the first-order
rate constant for the pH-independent reaction. Values of kH and ko are calculated to be
(1.1 ± 0.1) × 103 M-1s-1 and (3.3 ± 0.1) × 10-2 s-1, respectively.
2. Product Studies of the Hydrolysis of 5-Methoxyacenaphthylene 1,2-Oxide (47)
a. Acid-Catalyzed Reaction
A 25 µL aliquot of 47 in dioxane (1 mg/mL) was added to 2 mL of 0.1 M HClO4
in 50:50 dioxane/water, where >99% of the reaction is acid-catalyzed. The reaction
solution was allowed to stand at room temperature for 1.5 min and was then neutralized
to pH 5-8 with NaOH solution. The resulting solution was analyzed by reverse phase
- 26 -
HPLC on a C18 column with 50:50 methanol/water as eluting solvent (1.2 mL/min), and
products were monitored by UV detector at 265 nm. The retention times of cis diol 49,
trans diol 50, and ketone 48 were 10.7, 6.3, and 38.3 min, respectively, and the relative
yields were 62, 37, and ~1%, respectively.
b. pH-Independent Reaction
A 25 µL aliquot of 47 in dioxane (1 mg/mL) was added to 2 mL of 50:50
dioxane/water containing 2 × 10-3 M EPPS in which the pH was preadjusted to 7.65.
After the reaction solution was allowed to stand at room temperature for 2 min, the
solution was analyzed by HPLC under the conditions outlined in 2a above. The extinction
coefficient of ketone 48 at 265 nm was measured to be 3.1 times greater than the
extinction coefficients of diols 49 and 50. After correction for differences in extinction
coefficients of the products at 265 nm, the yields of 49, 50, and 48 were calculated to be
4, 2, and 94%, respectively. These product distributions are very similar to the product
distributions
from
the
acid-catalyzed
and
pH-independent
reactions
of
cyclopenta[cd]pyrene oxide 25.21
3. Acid-Catalyzed Equilibration of cis and trans Diols 49 and 50
A solution 1.2 mg of cis diol 49 in 2.5 mL of methanol was prepared. A portion of
this solution (0.75 mL) was added to 25 mL of 0.1 M HClO4 in water maintained at 25.0
± 0.2
C. At various times, 2 mL of the solution was removed, neutralized by addition
- 27 -
of 0.1 M NaOH, and analyzed
100
by HPLC under the conditions
noted above for product studies.
The
same
procedure
was
followed with the trans diol 53
as the starting material. At very
long reaction times (49 h), an
HPLC peak (~5%) with the
% Cis Diol
80
60
40
kobsd = (9.7  0.2) ¡Á10-2 h -1
20
0
0
kobsd = (9.7  0.4) ¡Á10-2 h -1
20
40
60
Time, Hr
80
100
Figure 6. Plots of pencent cis diol 49 vs time in
the equlibration reaction starting from either cis
diol 49 (  ) or trans diol 50 (  ) in 0.1 M
HClO4/water solution, 25  0.2 oC
same retention time as ketone
48 was observed. The isomerization results are summarized in Table 3, and the data were
plotted in Figure 6.
Table 3.
Ratio of cis diol 49 vs time in acid-catalyzed equilibration of cis and
tran diols 49 and 50 in 0.1 M HClO4, 25 ± 0.2 °C
Time, hour
0.00
0.55
1.52
3.50
5.67
7.67
11.0
14.0
24.0
33.0
49.0
57.0
78.0
% Cis Diol 49
100.0
95.5
88.5
78.3
66.3
57.7
46.7
39.8
26.3
22.8
20.3
19.5
19.2
- 28 -
% Cis Diol 49
0.00
1.9
3.2
5.6
7.9
9.5
11.6
13.3
16.1
17.2
17.8
18.8
19.0
The relative stabilities of cis and trans diols 49 and 50 were thus established by
the acid-catalyzed conversion of each diol to an equilibrium mixture of isomers (eq 2).
Cis diol (49) + H
+
k1
Trans diol (50) + H+
(2)
k-1
The approaches to an equilibrium mixture of cis and trans diols 49 and 50 in 0.1
M HClO4/water solutions at 25 ± 0.2 °C, starting from pure 49 and from pure 50, were
monitored by HPLC as functions of time. Plots of % cis diol vs. time for the approaches
to a cis:trans diol equilibrium mixture follow pseudo-first-order kinetics and are given in
Figure 6. The observed pseudo-first-order rate constant (kobsd) for approach to an
equilibrium from either side of Eq. 2 is equal to the sum of the forward and reverse
pseudo-first-order rate constants (k1[H+] + k-1[H+]) and are the same within experimental
error. Dividing kobsd by [H+] gives the average second-order rate constant of 0.96 M-1 h-1
for the acid-catalyzed approach to equilibrium (k1 + k-1). Extrapolation of the percent
composition vs time data in Figure 6 yields a calculated equilibrium mixture containing
81% of trans diol 50 and 19% of cis diol 49. At a much slower rate, the mixture of 52 and
50 reacts to form ketone 48. From the percentage of 49 and 50 at equilibrium,
K = k1/k-1 = 1.53. From equations k1/k-1 = 1.53 and (k1 + k-1) = 9.7 × 10-2 h-1, values of k1
and k-1 are calculated to be 5.9 × 10-2 h-1 and 3.8 × 10-2 h-1, respectively.
- 29 -
C. Discussion
1. Reactivities of 5-Methoxyacenaphthylene 1,2-Oxide 47 in Acid-Catalyzed and
pH-Independent Reactions
a. Acid-Catalyzed Hydrolysis of 47
The apparent second-order rate constants for acid-catalyzed epoxide hydrolysis do
not change significantly as a function of solvent composition in water/dioxane mixtures.
For example, kH for acid-catalyzed hydrolysis of 5-methoxyindene oxide in 1:3
dioxane/water is only ~14% smaller than in water. Approximate comparisons of
second-order
rate
constants
for
acid-catalyzed
hydrolysis
of
indene
oxides,
acenaphthylene 1,2-oxides, and cyclopenta[cd]pyrene oxide in dioxane/water solvents
that are somewhat different can therefore be made. However, the pH-independent
reaction of 5-methoxyindene oxide is 5.7 times slower in 1:3 dioxane/water than in water.
An increase of the percent of dioxane in a dioxane/water mixture therefore results in a
significant lowering of the rate of the pH-independent reaction.
Table 4 summarizes the rate constants for acid-catalyzed and pH-independent
reactions
of
styrene
oxides,
indene
oxides,
acenaphthylene
oxides,
and
cyclopenta[cd]pyrene oxide. Data from this table show that the substitution of a
p-methoxy group in place of hydrogen in styrene oxide results in an increase of kH in
water by 4.1 × 102 and an increase in ko by 7.1 × 102. Substitution of a methoxy group for
- 30 -
hydrogen in the 5-positions of indene oxide and acenaphthylene oxide results in an
increase in kH by factors of ~59 and ~34, respectively. The reduced substituent effects for
reactions of indene oxides and acenaphthylene oxides suggest "earlier" transition states
for their acid-catalyzed hydrolysis as compared to that for the acid-catalyzed hydrolysis
of styrene oxides. Compound 47 is somewhat less reactive than 5-methoxyindene oxide
but somewhat more reactive than cyclopenta[cd]pyrene oxide 25 toward acid-catalyzed
hydrolysis. The rate of the pH-independent reaction of 47 in 50:50 dioxane/water is only
slightly faster than the rate of the pH-independent reaction of 25 in 25:75 dioxane/water
but, with a correction for the difference in solvent, 47 is estimated to be approximately an
order of magnitude more reactive than 25 in the same solvent. In terms of both structure
and reactivity, 47 serves as an excellent model for cyclopenta[cd]pyrene oxide 25.
Table 4. Summary of kH and ko values for reactions of styrene oxides, indene oxides,
acenaphthylene oxides, and cyclopenta[cd]pyrene oxide in water and dioxane/water
solutions at 25 ± 0.2 °C
compd
kH (M-1 s-1)
ko (s-1)
compd
kH (M-1 s-1)
ko (s-1)
2.7 × 101
4.2 × 10-6
3.7 × 101
3.9 × 10-4
11aa
24d
1.1 × 104
3.0 × 10-3
1.1 × 103
3.3 × 10-2
11ba
47e
8.9 × 102
1.3 × 10-4
1.8 × 102
2.5 × 10-2
23ab
25f
5.2 × 104
5.2 × 10-2
23bc
a
Ref 30 (water). bRef 56 (water). cRef 38 (25:75 dioxane/water). dRef 21 (water). eThis work (50:50
dioxane/water). fRef 21 (25:75 dioxane/water).
O
O
X
11a. X=H
b (X=OCH3)
X
23a. X=H
b. X=OCH3
O
O
X
24 (X=H)
47 (X=OCH3)
- 31 -
25
b. pH-Independent Reaction of 47
The pH-independent reactions of 47 and 25 lead to 94% yields of isomeric
ketones 48 and 28, respectively, along with minor yields of cis and trans diols. The
transition states for rearrangement of 47 to ketone 4821 and of 25 to ketone 28 must have
considerable positive charge development on the benzylic carbons at the transition state,
because the benzylic C-O bond that undergoes cleavage in each system is the one leading
to the more stable carbocation. By analogy with the pH-independent reactions of
naphthalene
1,2-epoxide,37
p-methoxystyrene
oxide,57
and
6-methoxy-1,2,3,4-tetrahydronaphthalene-1,2-epoxide,58 this reaction most likely occurs
with 1,2-hydrogen migration to the electron-deficient benzylic carbon, possibly via a
concerted reaction.
2. Comparison of cis/trans Diol Product Ratio from Acid-Catalyzed Hydrolysis of 47
and Equilibrium cis/trans Diol Ratio for 49 and 50
The acid-catalyzed hydrolysis of both 47 and of 25 yields 60-62% of cis diol and
34-37% of trans diol, in addition to very minor yields of ketone products. However, trans
diol 50 is more stable than cis diol 49; therefore, acid-catalyzed hydrolysis of 47 yields
the less stable cis diol as the major product. Acid-catalyzed hydrolyses of
4-methoxyphenyloxirane (4-methoxystyrene oxide),30
trans-2-methyl-1-(4-methoxyphenyl)oxirane,59 and 5-methoxyindene oxide 23b38 occur
- 32 -
with rate-limiting epoxide ring opening to form discrete carbocation intermediates that
have sufficient lifetimes to react with external nucleophiles such as azide ion, and the
product-forming steps of each of these reactions are attack of water on the intermediate
Scheme 13.
cis attack
H3CO
OH
H+
H3CO
O
H
H3CO
H
OH
H
H
52
H+
trans attack
H
H
53
47
carbocation. It is therefore reasonable to assume that the acid-catalyzed hydrolysis of 47
occurs via a similar mechanism in which the product-forming steps are attack of water on
a discrete carbocation intermediate as shown in Scheme 13.
Although the epoxide group in 47 may undergo ring opening to give two different
benzylic carbocations, 52 and 53, the epoxide opening pathway shown in Scheme 13
leads to the more stable benzylic carbocation 53 that is better stabilized by the methoxyl
group. Density functional calculations at the B3LYP/6-31G* level of theory indicate that
carbocation 53 is 7.73 kcal/mol more stable than 52 in the gas phase and that there is a
single conformation for intermediate 53. Attack of water from one face of the carbocation
yields cis diol, and attack of water from the opposite face of the carbocation yields trans
diol. From the free energy diagram of the acid-catalyzed hydrolysis of 47, the differnence
in the relative transition state energies ∆G‡cis and ∆G‡trans (∆∆G‡) determines the
cis/trans diol product ratio. The transition state for cis attack of water on carbocation 53
must be stabilized by effects that are not present in the transition state for trans attack of
- 33 -
water on 53 (∆G‡cis < ∆G‡trans), even though cis attack of water leads to the less stable
cis diol product.
Energetically favored cis attack of solvent on the intermediate hydroxycarbocation
53 formed in the acid-catalyzed hydrolysis of 5-methoxyindene oxide has been attributed
Free
Energy (G)
in part to intramolecular hydrogen bonding between the attacking water molecule and the
G
Gtrans
O
Gcis
OCH3
OH
47
+ H+, H2O
OCH3
53
HO
OH
+ H2O
49
OCH3
HO
OH
+
+H
+ H+
50
OCH3
Reaction
Coordinate
Figure 7. Free energy diagram of the acid-catalyzed
hydrolysis of 47
- 34 -
β-hydroxyl group that is more favorable than hydrogen bonding between the attacking
water molecule and solvent in the transition state for trans attack38 A transition structure
for cis attack of water, calculated at the MP2/6-31G*//MP2/6-31G* level of theory, is
given by 54. In this structure, the H- - -O hydrogen bond distance between the incoming
water molecule and the adjacent hydroxyl oxygen atom is calculated to be 1.91Å, which
is within normal hydrogen bonding distance.60 Intramolecular hydrogen bonding between
the attacking water molecule and the adjacent hydroxyl group is not possible for trans
attack. The solvating effects of other water molecules and possibly different
transition state geometries may also contribute to the difference in transition state
energies for cis and trans attack of water on 53, but the magnitudes of these effects are
difficult to quantify.
- 35 -
D. Conclusions
Acid-catalyzed hydrolysis of 47 yields 49 as the major diol product and trans diol
50 as a minor product. However, acid-catalyzed equilibration studies show that trans diol
50 is more stable than cis diol 49. The mechanism proposed for the acid-catalyzed
reaction of 47 involves formation of an intermediate carbocation, followed by attack of
water from either side of the electron deficient benzylic carbon of the carbocation.
Transition state effects must selectively stabilize the transition state for attack of water on
the intermediate carbocation leading to the less stable cis diol. Because trans diol 50 is
more stable than its isomeric cis diol 49, it is reasonable to assume that trans diol 27 in
the cyclopenta[cd]pyrene system is more stable than its isomeric cis diol 26. Therefore,
transition state effects are also most likely responsible for the observation that
acid-catalyzed hydrolysis of 25 yields cis diol 26 as the major product. It is interesting to
note that the stereochemistry associated with acid-catalyzed hydrolysis of 25 is similar to
that of its reaction with DNA,61 which yields more cis than trans adducts. Although it is
not possible to extrapolate from solution chemistry to the reactions of 25 with DNA,
there are some important similarities. The benzylic C-O bond of the epoxide group in 25
leading to the more stable carbocation is cleaved in both the acid-catalyzed hydrolysis of
25 and in its reaction with DNA. Transition state effects may also play a role in
determining the stereochemistry of the reactions of 25 with DNA.
- 36 -
E. Experimental Procedures
1. Materials and Methods Dioxane and THF were distilled from sodium prior to use.
All other reagents were purchased from commercial sources. Quantum chemical
calculations were performed with the molecular modeling program Spartan04
(Wavefunction, Inc.). The pH values given throughout are those measured by the glass
electrode, and for 50:50 dioxane/water, they correspond to apparent pH values. The
activity of hydronium ion measured by the glass electrode was assumed to be equal to the
concentration of hydronium ion.
2. Synthesis
5-Nitro-1,2-dihydroacenaphthylene (41).45
To a rapidly stirred suspension of
acenaphthene 40 (10 g) in glacial acetic acid (80 mL) was added 70% HNO3 aq (12.5
mL) during 15 min. After the addition of HNO3 was done, the reaction mixture turned
yellow and was stirred for another 15 min. After filtration, the solid crude materials
(16.8g) were dissolved in ethyl acetate (100 mL) and washed twice with saturated
NaHCO3 solution (50 mL). The organic layer was separated, dried out with CaSO4, and
the solvent was removed on a rotoevap. The solid was dissolved and recrystallized from
ethyl acetate to give yellow needle crystals (9.8 g, yield 78.2%); mp 104 -105 ºC. (lit.45
mp 106 ºC) 1H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 8.2 Hz, 1H), 8.50 (d, J = 6.3 Hz,
- 37 -
1H), 7.71 (dd, J1 = 8.2 Hz, J2 = 6.3 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.31 (d, J = 7.3 Hz,
1H ), 3.47 (d, 4H) .
5-Amino-1,2-dihydroacenaphthylene (42).46
A mixture of nitro compound 41 (15.5 g,
0.078 mol), 225 mL of absolute ethanol, and 1.0 g of 10% Pd/C catalyst was charged into
a 500-mL bottle and shaken in a Parr hydrogenation apparatus at 60 psi. After 8 hours,
the reaction mixture was filtered to remove the catalyst, resulting clear solution. The
ethanol was removed at aspirator vacuum to yield 13.0 g of gray solid (yield 98.7%). The
crude product (2.4 g) was dissolved in 28 mL of cyclohexane and recrystallized to yield
1.9 g of gray needle crystals. mp 103-105 ºC (lit.46 mp 104 ºC ) 1H NMR (400 MHz,
CDCl3): δ 7.45 (d, J = 8.1 Hz, 1H), 7.4 (dd, J1 = 8.1 Hz, J2 = 7.2, 1H), 7.3 (d, J = 7.2 Hz,
1H), 7.07 (d, J = 6.9 Hz, 1H), 6.77 (d, J = 6.9 Hz, 1H), 3.99(b, 2H), 3.39 (m, 4H)
5-Methoxy-1,2-dihydroacenaphthylene
(45).62
A
suspension
of
0.95
g
5-aminoacenaphthene 45 in 30 g of 10% sulfuric acid was heated in a sealed pressure
tube at 200  5 C for 4 hours. 43 The solution was cooled down to room temperature. The
black solid was collected by filtration, dissolved in 50 mL of 2 M potassium hydroxide
solution, and heated to boiling. The solution was filtered after it cooled. The resulting
clear solution was stirred with 5 mL of dimethylsulfate overnight. The next day, the
solution was brought to boiling for 2 hours to destroy the remaining dimethylsulfate. The
solution was extracted with 50 mL of diethyl ether twice, and the combined organic
extracts were dried over calcium sulfate. The ether was removed to yield 0.53 g brown
oil, which solidified slowly in the air (yield 51.2%). The solid was sublimed (0.2
- 38 -
mmHg) to yield yellow crystals. mp 60-61C (lit.63 mp 66C.). 1H NMR (400 MHz,
CDCl3): δ 7.8 (d, J=8.2, 1H,), 7.43 (dd, J1=8.2, J2 = 6.9, 1H), 7.26 (d, J=6.9, 1H), 7.17
(d, J=7.6, 1H), 6.79 (d, J=7.6, 1H,), 3.99(s, 3H), 3.39(m, 4H,).
5-Methoxyacenaphthylene (46). Compound 45 (100 mg) was dissolved in 6 mL of
benzene, and 147 mg of dichlorodicyanobenzoquinone (DDQ) was added to the solution.
The mixture was heated at reflux for 2 h. The reaction mixture was then cooled and
filtered through alumina III (6% H2O). The solvent was removed by rotary evaporation to
yield 65 mg (66%) of yellow crystals; mp 62-63 C. 1H NMR (400 MHz, CDCl3): δ 8.05
(d, J = 8.2 Hz, 1H), 7.66 (d, J = 6.9 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.50 (dd, J1 = 6.9
Hz, J2 = 8.2 Hz, 1H), 6.99 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 5.1 Hz, 1H), 6.75 (d, J = 7.3
Hz, 1H), 3.94 (s, 3H). Anal. calcd for C13H12O: C, 85.69; H, 5.53. Found: C, 85.51; H,
5.49. MS (EI) m/z 182 (M+).
5-Methoxyacenaphthylene 1,2-Oxide (47). A solution of 5.0 mg of 46 in 0.25 mL of
acetone-d6 was precooled in a dry ice/ethylene glycol bath, and a solution of
dimethyldioxirane in 0.75 mL of acetone-d6 was added. The reaction solution was kept in
the dry ice/ethylene glycol bath for another 10 min, at which time the color of the
solution turned from yellow to colorless. 1H NMR spectrum (400 MHz, acetone-d6) δ
7.89 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.42 (dd, J1 =
6.9 Hz, J2 = 8.2 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 4.85(d, J = 2.7 Hz, 1H), 4.80 (d, J =
2.7 Hz, 1H), 3.96 (s, 3H). HRMS (FAB) calcd for C13H11O2+ [M + H+] m/z 199.0759;
- 39 -
found, 199.0778. This product was used for kinetic and product studies without further
purification.
5-Methoxy-1,2-dihydroacenaphthylene-cis-1,2-diol (49). A solution of 100 mg of 46
and 140 mg of osmium tetroxide in 10 mL of pyridine was stirred at room temperature
for 4 h. A water solution of 0.3 g of sodium bisulfite was added, and the reaction mixture
was stirred overnight. The mixture was extracted twice with 25 mL of ethyl acetate. The
ethyl acetate extracts were combined, and the combined ethyl acetate solution was
washed with 15 mL of 2 M HCl and 30 mL of saturated sodium bicarbonate solution. The
ethyl acetate solution was dried over calcium sulfate, and the solvent was removed to
yield 117 mg of crude product. This material was sublimed at 120 C (0.02 mmHg) to
yield 40.6 mg (34%) of white solid, which was recrystallized from ethyl acetate/diethyl
ether to yield 27 mg (23%) of 52; mp 172-173 °C. 1H NMR (400 MHz, DMSO-d6): δ
7.81 (d, J = 8.2 Hz, 1H), 7.50 (apparent t, J1 + J2 = 15.1 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H),
7.36 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 5.26-5.19 (apparent m, 3 H), 5.13 (d, J
= 6.8 Hz, 1H), 3.93 (s, 3H). Anal. calcd for C13H12O3: C, 72.21; H, 5.59. Found: C, 72.11;
H, 5.47.
5-Methoxy-1,2-dihydroacenaphthylene-trans-1,2-diol (50). A solution of 139 mg of
iodine in 2.5 mL of benzene was added to a mixture of 251 mg of silver benzoate in 2.5
mL of benzene. The mixture was stirred for 30 min. Compound 46 (100 mg) in 1.0 mL of
benzene was added dropwise, and the reaction mixture was stirred for 4 h under nitrogen.
- 40 -
The reaction mixture was filtered, and the solvent was removed to give 256 mg of crude
dibenzoate diester. To this product was added a solution of 2.5 mL of 6.7 M KOH and 25
mL of methanol. The aqueous methanolic KOH reaction solution was heated at reflux for
1.5 h. The reaction solution was cooled, and most of the methanol was removed by rotary
evaporation. Water (25 mL) was added, and the mixture was extracted twice with 20 mL
of ethyl acetate. The combined ethyl acetate solution was dried over calcium sulfate, and
the solvent was removed to yield 137 mg of a crude product containing both trans diol 50
and cis diol 49 (trans/cis ratio 70:30). The crude product mixture was sublimed at 110 ºC
(0.02 mmHg), and the sublimate was recrystallized from diethyl ether/ethyl acetate to
yield 20 mg of a solid material that was still a mixture of ~70% trans diol and ~30% cis
diol. A sample of 13 mg of pure trans diol 7 was isolated by preparative HPLC on a C18
column with 60% methanol/40% water as eluting solvent; mp 155-156 ºC. 1H NMR (400
MHz, DMSO- d6): δ 7.83 (d, 1H, J = 8.2 Hz), 7.52 (apparent t, 1H, J1 + J2 = 15.1 Hz),
7.44 (d, J = 6.8 Hz, 1H), 7.34 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 5.81 (d, J =
6.4 Hz, 1H), 5.70 (d, J = 6.4 Hz, 1H), 5.15 (dd, J1 = 6.4 Hz, 1H), 5.13 (dd, J = 6.4 Hz,
1H), 3.95 (s, 3H). Anal. calcd for C13H12O3: C, 72.21; H, 5.59. Found: C, 72.12, H, 5.56.
5-Methoxy-1,2-dihydroacenaphthylen-1-one (48). Compound 47 (7.1 mg) was
dissolved
in
3
mL
of
50:50
H2O/THF
containing
2
mM
EPPS
[(N-2-hydroxyethyl)piperazine-N'-3-propanesulfonic acid] at pH 7.65. After 5 min, the
THF was removed, and the product was extracted into ethyl acetate. The organic layer
- 41 -
was dried over Na2SO4, and the solvent was removed to yield 4.9 mg (69%) of yellow
crystals. The crude product was recrystallized from ethyl acetate/diethyl ether solution to
yield 2.1 mg of product; mp 142-144 ºC. 1H NMR (CDCl3, 400 MHz): δ 8.32 (d, J = 8.2
Hz, 1H), 7.95 (d, J = 7.3 Hz, 1H), 7.67 (apparent t, J1 + J2 = 15.1 Hz, 1H), 7.34 (d, J =
7.3 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.03 (s, 3H), 3.74 (s, 2H). Anal. calcd for C13H10O2:
C, 78.77; H, 5.09. Found: C, 78.66, H, 4.91.
The structure of 48 was confirmed by 1H NOE and decoupling experiments. The
absorption of H-7 occurs as a doublet of doublets at δ7.67. Saturation of this absorption
resulted in the simplification of absorptions at δ7.95 and δ 8.32 from doublets to singlets;
therefore, these two absorptions can be assigned to H-6 and H-8. The absorptions at δ6.86
and δ7.34 can be assigned to H-4 and H-3, respectively, because of the shielding effect of
the methoxyl group. Irradiation of the absorption at δ6.86 led to NOE enhancements of
only the absorption at δ7.34 and the methoxyl hydrogen absorption at δ4.03; thus, the
absorption at δ6.86 was assigned to H-4. Irradiation of the absorption at δ7.34 also led to
NOE enhancements of the H-4 absorption at δ6.86 and the methoxyl hydrogen absorption
at δ4.03 but in addition led to an NOE enhancement of the benzylic H-2 absorption at
δ3.74. These NOE observations confirm that the methylene C-2 hydrogens are benzylic
to the phenyl ring containing the methoxyl group.
- 42 -
NO2
H NMR (400 MHz, CDCl3): δ 8.56 (d, J=8.2, 1H), 8.504 (d, J=6.3, 1H), 7.71 (dd, J1 = 8.2, J2 = 6.3, 1H), 7.45 (d,
J=7.3, 1H), 7.31 (d, J= 7.3, 1H), 3.47 (d, 4H)
1
- 43 -
NH2
H NMR (400 MHz, CDCl3): δ 7.45 (d, J=8.1, 1H), 7.4 (dd, J1=8.1, J2 = 7.21H), 7.3 (d, J=7.2, 1H), 7.07 (d, J=6.9,
1H), 6.77 (d, J=6.9, 1H), 3.99(b, 2H), 3.39 (m, 4H)
1
- 44 -
OCH3
H NMR (400 MHz, CDCl3): δ 7.8 (d, J=8.2, 1H,), 7.43 (dd, J1=8.2, J2 = 6.9, 1H), 7.26 (d, J=6.9, 1H), 7.17
(d, J=7.6, 1H), 6.79 (d, J=7.6, 1H,), 3.99(s, 3H), 3.39(m, 4H,).
1
- 45 -
OCH3
H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 6.9 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.50
(dd, J1 = 6.9 Hz, J2 = 8.2 Hz, 1H), 6.99 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 5.1 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H),
3.94 (s, 3H).
1
- 46 -
O
OCH3
H NMR spectrum (400 MHz, acetone-d6) δ 7.89 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 7.3 Hz,
1H), 7.42 (dd, J1 = 6.9 Hz, J2 = 8.2 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 4.85(d, J = 2.7 Hz, 1H), 4.80 (d, J = 2.7 Hz,
1H), 3.96 (s, 3H).
1
- 47 -
HO
OH
OCH3
H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J = 8.2 Hz, 1H), 7.50 (apparent t, J1 + J2 = 15.1 Hz, 1H), 7.45 (d, J = 6.8
Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 5.26-5.19 (3 H), 5.13 (d, J = 6.8 Hz, 1H), 3.93 (s, 3H).
1
- 48 -
HO
OH
OCH3
H NMR (400 MHz, DMSO- d6): δ 7.83 (d, J = 8.2 Hz, 1H), 7.52 (apparent t, J1 + J2 = 15.1 Hz, 1H), 7.44 (d, J = 6.8
Hz, 1H), 7.34 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 5.81 (d, J = 6.4 Hz, 1H), 5.70 (d, J = 6.4 Hz, 1H), 5.15
(dd, J1 = 6.4 Hz, 1H), 5.13 (dd, J = 6.4 Hz, 1H), 3.95 (s, 3H)..
1
- 49 -
O
OCH3
H NMR (CDCl3, 400 MHz): δ 8.32 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 7.3 Hz, 1H), 7.67 (apparent t, J1 + J2 = 15.1
Hz, 1H), 7.34 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.03 (s, 3H), 3.74 (s, 2H).
1
- 50 -
OCH3
Anal. calcd for C13H12O: C, 85.69; H, 5.53. Found: C, 85.51; H, 5.49. MS (EI) m/z 182 (M+).
- 51 -
O
OCH3
HRMS (FAB) calcd for C13H11O2+ [M + H+] m/z 199.0759; found, 199.0778.
- 52 -
Chapter III
Hydrolysis of Hydrolysis of 7-Methoxynaphthalene
1,2-oxide (61), 7-Methoxy-1-deuterionaphthalene
1,2-Oxide (61-1 d) and 6-Methoxynaphthalene
1,2-Oxide (68)
- 53 -
A. Results
1. Synthesis of 7-Methoxynaphthalene 1,2-Oxide (61),
7-Methoxy-1-deuterionphthalene 1,2-oxide (61-1d) and 6-Methoxynaphthalene
1,2-Oxide (68)
The starting material for the synthesis of 7-methoxynaphthalene 1,2-oxide 61 is
7-methoxy-1-tetralone 55. Reduction of 55 by lithium aluminum hydride in absolute
ether afforded 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol 56,64 which undergoes
acid-catalyzed dehydration to give 7-methoxy-3,4-dihydronaphthalene 57.65 Reaction of
57
with
N-bromoacetamide
in
2-bromo-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol
THF/water
58.66
yielded
Compound
58
was
converted to trifluoroacetate 59, which was brominated in carbon tetrachloride with
N-bromosuccinimide to give 2,4-dibromo-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl
ester 60. In the final step, the dibromoester 60 was treated with sodium methoxide
(powder) in dry THF to give the final target epoxide 7-methoxynaphthalene 1,2-oxide 61.
O
H3CO
i
H3CO
ii
F3COCO
H(D)
Br
H3CO
59
H CO
iii 3
H(D)
H3CO
Br vi
60
Br
H(D)
Br
58
57
F3COCO
v
HO
H3CO
56
55
iv
H(D)
H(D)
HO
O
H3CO
61
D
H3CO
O
61-1d
Reagents and conditions: (i) LiAlH4 or LiAlD4 absolute ether (ii) Toluenesulfonic acid, toluene, (iii) NBA, THF/water (3:1),
(iv) (CF3CO)2O, (v) NBS, CCl4, (vi) NaOCH3, THF.
Scheme 14. Synthesis of 7-methoxynaphthalene 1,2-oxide
- 54 -
In the synthesis of the corresponding deuterium compound, in step i, LiAlD4 instead of
LiAlH4 was used, and the rest of the steps were the same.
The synthesis of 6-methoxynaphthalene 1,2-oxide 68 is very similar for that of 61,
except that bromohydrin 65 was converted to an acetate ester instead of a trifluoroacetate
ester because the corresponding trifluoroacetoxy compound is not stable at room
temperature. Another change is in the bomination of 66 with NBS. The two benzylic
positions have almost equal reactivity toward bromine radicals; the target dibromide 67
had to be isolated by column chromatography.
OH
O
OH
i
H3CO
H3CO
H3CO
62
63
OCOCH3
Br
iv
H3CO
OCOCH3
Br
v
H3CO
66
Br
iii
ii
67
H3CO
64
65
O
vi
H3CO
Br
68
Reagents and conditions: (i) LiAlH4, absolute ether (ii) Toluenesulfonic acid, toluene, (iii) NBA, THF/water (3:1),
(iv) Ac2O, (v) NBS, CCl4, (vi) NaOCH3, THF.
Scheme 15. Synthesis of 6-methoxynaphthalene 1,2-oxide
Both epoxides 61 and 68 were prepared as colorless solids. They are stable in
solution (THF or acetone), but solid samples of these epoxides isomerize at room
temperature within a day or so to form phenols. High resolution mass spectra along with
1
H NMR spectra confirmed their identities. Epoxide 61 and 68 were dissolved in
acetone-d6 immediately after they were prepared, and their 1H NMR spectra were
- 55 -
recorded. The acetone-d6 solution of 61 and 68 were used directly for kinetic and product
studies.
The synthesis of naphthalene 1,2-oxide (75) was accomplished according to a
published procedure.67 The chemical steps and reagents are listed in Scheme 16. The
NMR spectra of the products were recorded and compared with the published spectra.
Naphthalene oxide was isolated in the form of white solid (mp. 42-43 °C，mp. lit.68
41-42°C) This solid was dissolved in acetone-d6 for kinetic measurements.
O
HO H
OH
iii
ii
i
70
69
O
iv
73
71
72
O
v
O
vi
74 Br
Br
75
Reagents and conditions: (i) LiAlH4, absolute ether (ii) Toluenesulfonic acid, toluene, (iii) NBA, THF/water (3:1),
(iv) Powder KOH (v) NBS, CCl4, (vi) DBN, THF.
Scheme 16. Synthesis of naphthalene 1,2-oxide
2. Kinetic Studies of Substituted Naphthalene Oxides 61 and 68
For each kinetic run, approximately 10-15 μL of a stock solution of 61 in
acetone-d6 (1 mg/mL) was added to 2.0 mL of 50:50 dioxane/water, 0.1M NaClO4
solution in the thermostated cell compartment (25.0 ± 0.2 °C) of a UV-vis
spectrophotometer. Reactions were monitored at 244 nm, and pseudo-first-order rate
constants were calculated by nonlinear regression analysis of the absorbance vs time data.
- 56 -
The data are summarized in Table 5. In monitoring the rates of hydrolysis of 71, the same
procedure was followed. The results are summarized in Figure 7. In this solvent,
acid-catalyzed hydrolysis occurs at pH < ~5, and a pH-independent reaction occurs at
pH > ~5. Rate data were fit to the equation kobsd = kH[H+] + ko, where kH is the
second-order rate constant for the acid-catalyzed hydrolysis reaction of 61, and k0 is the
first-order rate constant of the pH-indepent reaction of 61. Plots of log kobsd vs. pH for
reaction of 61 and 68 are shown in Figure 7. Values of kH and k0 are calculated to be
(4.32 ± 0.17)×102 M-1s-1 and
(1.19 ± 0.03) × 10-2 s-1 for 61 and (9.36 ± 0.30 )×102 M-1s-1
and (5.52 ± 0.13) × 10-3 s-1 for 68. The acid-catalyzed reaction of 61 is slower than that of
68, but the rate of pH-independent reaction of 61 is approximately twice as fast as that of
68.
Table 5. Observed rate constants as a function of pH for hydrolysis of 61 in 50:50
dioxane/water in 0.1 M NaClO4, 25 ± 0.2 °C
Buffer, 0.002 M
No Buffer
No Buffer
CAPS
CHES
EPPS
MOPSO
MES
MES
MES
No Buffer
No Buffer
No Buffer
No Buffer
No Buffer
kobsd × 102, s-1
1.183
1.128
1.195
1.229
1.213
1.152
1.223
1.394
1.401
2.056
4.259
5.004
7.132
10.39
pH
12.45
11.93
10.07
9.0
8.28
7.17
6.00
5.35
5.24
4.54
4.21
4.04
3.91
3.63
- 57 -
% Error
1.15
2.28
0.83
0.62
0.64
1.07
0.32
0.53
0.47
0.42
0.64
0.62
0.82
0.66
Table 6. Observed rate constants as a function of pH for hydrolysis of 68 in 50:50
dioxane/water in 0.1 M NaClO4, 25 ± 0.2 °C
Buffer, 0.002 M
No Buffer
No Buffer
CAPS
CHES
EPPS
MOPSO
MES
MES
No Buffer
No Buffer
No Buffer
No Buffer
No Buffer
kobsd × 103, s-1
5.645
5.912
5.757
5.749
5.401
5.599
6.210
8.366
12.31
25.31
43.11
115.5
309.4
pH
12.42
11.14
10.14
8.98
8.00
7.03
5.89
5.44
5.16
4.62
4.40
3.96
3.52
- 58 -
% Error
1.15
2.28
0.83
0.62
0.64
1.07
0.32
0.53
0.47
0.97
0.42
0.64
0.62
Figure 7. Plot of log k obsd for reactions of 61 (  ) and 68 (  )
vs apparent pH, 50:50 dioxane/water, 0.1M NaClO 4, 25  0.2 C
Log k obsd
-0.5
-1.0
-1.5
-2.0
-2.5
4
6
8
10
12
pH
3. Solvent Effect on kH and k0 for the Hydrolysis of 61
The method summarized in Part 2 was used for the measurement of the rates of
reaction of epoxide 61 in 50:50 dioxane/water, 40:60 dioxane/water and 30/70
dioxane/water. Rate data were fit to the equation kobsd = kH[H+] + k0, and the results are
summarized in Tables 7, 8 and 9. Plots of log kobsd vs. pH for reaction of 61 are shown in
Figure 8. Values of kH and ko are summarized in Table 10.
Buffer, 0.002 M
kobsd × 102, s-1
pH
- 59 -
% Error
CHES
9.50
1.31of pH for hydrolysis
0.51of 61
Table 7. Observed rate
constants as a function
CHES
8.90-8.91
0.53
in 50:50 dioxane/water
in 0.1 M NaClO4, 251.33
± 0.2 °C
a
MOPSO
7.20
1.10
0.54
MOPSO
7.01
1.32
0.24
MES
6.21-6.23
1.37
0.76
No Buffer
5.27-5.30
1.76
0.30
No Buffer
4.73
2.34
0.40
No Buffer
4.49-4.53
2.68
0.58
a
In this kinetic run, NaClO4 was not added to the solution.
Table 8. Observed rate constants as a function of pH for hydrolysis of 61
in 40:60 dioxane/water, 0.1 M NaClO4, 25 ± 0.2 °C
Buffer, 0.002 M
CHES
MOPSO
MES
No Buffer
No Buffer
No Buffer
kobsd × 102, s-1
4.24
4.14
4.03
4.27
6.31
8.73
pH
9.50
7.27
6.54
5.23
4.73-4.75
4.27-4.31
% Error
0.32
0.17
0.74
0.43
0.59
0.76
Table 9. Observed rate constants as a function of pH for hydrolysis of 61
in 30:70 dioxane/water, M NaClO4, 25 ± 0.2 °C
- 60 -
Buffer, 0.002 M
CHES
HEPES
MOPSO
MOPSO
No Buffer
No Buffer
pH
9.20
7.76
6.99
6.79
5.33-5.35
4.56-4.57
kobsd × 101, s-1
1.20
1.18
1.19
1.18
1.23
1.53
% Error
0.42
1.43
0.54
0.51
0.54
0.68
Figure 8. Rate-pH Profiles for Hydrolysis of 61 in
Various Dioxane-water Solutions,
0.1M NaClO4, 25 ± 0.2 OC
0.0
Log kobsd
-0.5
-1.0
-1.5
-2.0
3.5
4.5
5.5
6.5
- 61 pH
7.5
8.5
9.5
Table 10. Rate constants for hydrolysis of 61 in dioxane-water solutions,
0.1 M NaClO4, 25 ± 0.2 °C
4. Isotope Effects on the Acid-catalyzed Hydrolysis and pH-independent reaction of
61 and 61-1d
a. Rate-pH Profiles of 61 and 61-1d
Solvent
kH (M-1s-1)
ko (s-1)
30:70 Dioxane-H2O
40:60 Dioxane-H2O
50:50 Dioxane-H2O
( 1.24 ± 0.05)×103
( 8.76 ± 0.69 ) ×102
(4.74.± 0.33 ) ×102
( 1.19 ± 0.04 ) × 10-1
( 4.05 ± 0.10) × 10-2
(1.35 ± 0.03) × 10-2
- 62 -
Buffer, 0.002 M
pH
kobsd × 102, s-1
% Error
EPPS
EPPS
MOPSO
MES
MES
No buffer
No Buffer
No Buffer
7.86
7.46
6.86
6.29
5.72
4.68
3.86
3.58
1.015
1.006
1.031
1.003
1.059
1.598
6.383
11.91
0.18
0.25
0.15
0.53
0.56
0.43
0.25
0.30
In the same method used for determining the pH-rate profiles for reaction of 64
and 61-1d, 10-15 μL of stock solutions of 61 or 61-1d in acetone-d6 (1 mg/mL) were
added to 2.0 mL of 50:50 dioxane/water solution at the temperature of 25.0 ± 0.2 °C in a
Gilford Response UV-vis spectrophotometer. The rate data are summarized in Tables 11
and 12. The rate-pH profiles of 61 and 61-1d are shown in Figure 9. All the data were
Table
11.same
Observed
rate constants
as vs.
a function
pH forofhydrolysis
of 61in Figure
collected
in the
day. Plots
of log kobsd
pH for of
reaction
61 are shown
in 50:50 dioxane/water in 0.1 M NaClO4 25 ± 0.2 °C
9. Values of kH and k0 are calculated to be (3.87 ± 0.19)×102 M-1s-1 and (1.00 ± 0.03) ×
10-2 s-1 for 61, and (3.97 ± 0.30)×102 M-1s-1 and (8.95± 0.37) × 10-3 s-1 for 61-1d. These
data give a good estimation of the kinetic deuterium isotope effect for the
pH-independent reaction, but not for the acid-catalyzed reaction. More precise isotope
effects on both the acid-catalyzed and pH-independent reaction were determined by a
different procedure outlined in the next section.
- 63 -
Table 12. Observed rate constants as a function of pH for hydrolysis of
61-1d in 50:50 dioxane/water in 0.1 M NaClO4, 25 ± 0.2 °C
Buffer, 0.002 M
EPPs
EPPs
MOPSO
MES
MES
N/A
N/A
N/A
kobsd × 102, s-1
0.901
0.925
0.955
0.902
0.907
1.456
6.742
12.05
pH
7.86
7.46
6.86
6.29
5.72
4.68
3.86
3.58
% Error
0.27
0.18
0.21
0.11
0.28
0.18
0.41
0.27
Figure 9. Plot of kobsd for reactions of 61 (  ) and 61-1d (  )
vs apparent pH, 50:50 dioxane/water, 0.1M NaClO4, 25  0.2 C
Log kobsd
-0.5
-1.0
-1.5
-2.0
-2.5
3.5
6.0
8.5
11.0
13.5
pH
b. Kinetic Isotope effects on the the Acid-catalyzed Hydrolysis and pH-independent
reaction of 61 and 75
- 64 -
In an experiment to determine an accurate kinetic isotope effect k0(H)/k0(D) for
the pH-independent reaction of 61, a 50 mL solution of dioxane:water (50:50) with 0.1 M
NaClO4 at pH 7.28 with 0.002 M HEPS was prepared. The rates for the pH-independent
reaction of 61 and 61-1d in this solution were determined in the following procedure.
Four cuvettes, each containing the reaction solution, were allowed to come to temperature
at 25 °C in a UV-Vis spectrophotometer. The rate of 61 was monitored first, then in
succession the rate of 61-1d, 61 and 61-1d were monitored. Individual values of
k0(H)/k0(D) were determined by comparing the rate of 61 in cell 1 vs. the rate of 61-1d in
cell 2 and the rate of 61 in cell 3 vs. 61-1d in cell 4. This procedure was repeated to
obtain additional values of k0(H)/k0(D). The observed values of k0(H)/k0(D) are 1.080,
1.088, 1.119, 1.075, 1.092, and 1.090, from which an average isotope effect k0(H)/k0(D)
is calculated to be 1.09 ± 0.01.
In another experiment to determine an accurate isotope effect kH (61) / kD (61-1d) ,
a 50 mL solution of dioxane:water (50:50) with 0.1 M NaClO4 at pH 3.78 was prepared.
At this pH, the hydrolysis of 61 is 89.4% acid-catalyzed and the hydrolysis of 61-1d is
90.5% acid-catalyzed. The rates for the acid-catalyzed hydrolysis of 61 and 61-1d in this
solution were also determined in pairs as described above. The isotope effects observed
for the reaction of 61 and 61-1d are 0.970, 0.974, 0.962, 0.967, 0.950, and 0.983. Taking
their average of values gave kH (61) / kH (61-1d) = 0.97 ± 0.01. After correction for the
11% of pH-independent reaction, the isotope effect kH (61) / kH (61-1d) = 0.96 ± 0.01
- 65 -
The kinetic isotope effects on the acid-catalyzed hydrolysis reaction of the
methoxy substituted naphthalene 1,2-oxide 61 is slightly inverse, which is not in
agreement with the published result (kH(75)/kD(75-1d) = 1.06 for naphthalene
1,2-oxide).69 In order to determine if the methoxy group changes the kinetic isotope
effects of the acid-catalyzed hydrolysis of naphthalene 1,2-oxide from “normal”, the
naphthalene 1,2-oxide (75) and 1-deuterionaphthalene 1,2-oxide (75-1d) were prepared
and their rates in acid-catalyzed hydrolysis and pH-independent reactions were measured
in water following the same procedure above in determination of the kinetic isotope
effects for 61 and 61-1d. The observed values of k0(75)/k0(75-1d) are 1.085, 1.067, 1.092,
1.086, 1.086, and 1.081, from which an average isotope effect k0(H)/k0(D) is calculated to
be 1.08 ± 0.01. The isotope effects observed for the reaction of 75 and 75-1d are 0.968,
0.951, 0.969, 0.952, 0.939, and 0.925. Taking their average of values gave kH (75) / kH
(75-1d) = 0.95 ± 0.01. After correction for the 5 % of pH-independent reaction, the
isotope effect kH (75) / kH (75-1d) = 0.94 ± 0.01
5. Substituent Effects on the Hydrolysis of Naphthalene 1,2-oxide (75)
- 66 -
The rates for both acid-catalyzed hydrolysis and pH-independent reaction of
naphthalene 1,2-oxide (75) were measured in 50:50 dioxane/water, 0.1M NaClO4, 25 ±
0.2 °C. Plots of log kobsd vs. pH are shown in Figure 10. Values of kH and k0 were
determined to be 19 ± 1 M-1s-1and (7.1 ± 0.7) × 10-6 s-1, respectively. The data are
summarized in Table 13. 7-Methoxynaphthalene 1,2-oxide (61) reacts 20 times faster
than the unsubstituted naphthalene 1,2-oxide in the acid-catalyzed hydrolysis, but 1400
times faster in the pH-independent reaction.
Table 13. Observed rate constants as a function of pH for hydrolysis of 75
in 50:50 dioxane/water in 0.1 M NaClO4 25 ± 0.2 °C
Buffer, 0.002 M
EPPS
EPPS
MES
MES
No Buffer
No buffer
No Buffer
No buffer
No Buffer
No buffer
pH
7.86
7.37
6.22
5.69
4.58
3.85
3.59
3.41
3.24
2.86
kobsd × 103, s-1
0.00821
0.00784
0.01677
0.04360
0.7206
2.450
4.530
7.080
12.14
26.23
- 67 -
% Error
0.95
1.27
0.32
0.12
0.16
0.27
0.13
0.18
0.21
0.35
Figure 10. Plot of log k obsd for reaction of 76 vs apparent pH,
50:50 dioxane/water, 0.1M NaClO4, 25 ± 0.2 oC
Log kobsd
0.025
0.015
0.005
-0.005
2.5
4.5
6.5
8.5
10.5
12.5
pH
6. Solvent Isotope Effects on the Acid-catalyzed Hydrolysis and pH-Independent
Reaction of 61
The rates for both acid-catalyzed hydrolysis and pH-independent reactions of 61
were determined in 50:50 D2O/Dioxane. These data are summarized in Table 12, and the
rate-pH profiles for reaction 61 in both 50:50 H2O/dioxane and 50:50 D2O/dioxane are
shown in Figure 11. The pH’s measured by the glass electrode are apparent pH values.
From the literature, pD = pH + 0.4.70 The data are summarized in Table 14. The solvent
isotope effect for the acid-catalyzed hydrolysis of 61 kH(H2O)/kH(D2O) is calculated to be
0.57 ± 0.05, and for the pH-independent reaction, k0 (H2O)/k0 (D2O) is calculated to be
1.16 ± 0.06.
- 68 -
Table 14. Observed rate constants as a function of pH for hydrolysis of 61 in 50:50
dioxane/H2O in 0.1 M NaClO4, 25 ± 0.2 °C
Buffer, 0.002 M
No Buffer
CHES
MOPSO
MES
No buffer
No buffer
No Buffer
No Buffer
kobsd × 102, s-1
0.9480
1.113
1.167
1.105
1.132
1.382
3.450
10.34
pH
13.45
8.92
6.96
5.99
5.20
4.84
3.99
3.40
% Error
0.11
0.15
0.24
0.21
0.15
0.27
0.34
0.28
Table 15. Observed rate constants as a function of pH for hydrolysis of 61 in 50:50
dioxane/D2O in 0.1 M NaClO4, 25 ± 0.2 °C
Buffer, 0.002 M
CHES
CHES
No Buffer
No Buffer
No Buffer
No buffer
kobsd × 102, s-1
0.8746
0.8987
1.011
1.605
5.905
8.315
pD
9.50
8.39
5.47
4.86
3.95
3.70
- 69 -
% Error
0.30
0.14
0.22
0.14
0.32
0.55
Figure 11. Plot of log k obsd for reactions of 61 in 50:50 H2O/Dioxane (  )
and 50:50 D2O/Dioxane (  ) vs apparent pH (pD),
0.1 M NaClO4, 25  0.2 C
Log kobsd
-0.5
-1.0
-1.5
-2.0
-2.5
4.0
6.5
9.0
11.5
14.0
pH
7. Product Studies of the Hydrolysis Reactions of 61 and 68
a. HPLC Product Studies
A 25 μL aliquot of 61 in acetone-d6 was added to 2 mL of 50:50 dioxane/water
with an apparent pH of 2.0 pre-adjusted with HClO4 solution (1.0 M). Before adding the
substrate, the solvent was deoxygenated by bubbling nitrogen through it. Under these
conditions, >99% of the reaction is acid-catalyzed. An aliquot of the epoxide solution
was added, and the reaction solution was shaken and allowed to stand at room
temperature for 10 seconds. It was then neutralized to pH 5-8 with NaOH solution. The
resulting solution was analyzed by reverse phase HPLC on a C18 column with 30:70
- 70 -
methanol/water as eluting solvent (1.0 mL/min), and the products were monitored by UV
detector at 277 nm. Only one major product (1-naphthol, > 99%) eluted as a broad peak
with a retention time of 23.2 min. In the same condition, acid-catalyzed hydrolysis of
epoxide 71 give only 2-naphthol product (> 99%), retention time 22.3 min.
A 25 μL aliquot of 61 in acetone-d6 was added to 2 mL of deoxygenated 50:50
dioxane/water containing 2 ×10-3 M MOPSO in which the pH was adjusted to be 7.15,
where the reaction is > 99% pH-independent. The reaction solution was allowed to stand
for 2 min, and it was then analyzed by HPLC under the conditions outlined above. The
product (>99%) was exclusively 1-naphthol. Following the same procedure, the
pH-independent reaction of 71 yielded only 2-naphthol (>99%).
b. Semi-preparative Reactions: 1H NMR Identification of the Hydrolysis Products of
61, 61-1d and 68
In a semi-preparative reaction, 1 mL of epoxide 61 (~ 5 mg/mL) in acetone-d6
was quickly injected into 10 mL of vigorously stirred 0.0l M HClO4 water solution. The
reaction solution was allowed to stand at rt for 30 min, and it was then extracted twice
with 15 mL of diethyl ether. The combined ether layers were dried over Na2SO4, and the
solvent was removed with a rotary evaporator. The residue was dissolved in CDCl3, and
its 1H NMR spectrum was recorded. The spectrum was identical with that of a
commercial sample of 1-naphthol. Following the same procedure, the acid-catalyzed
- 71 -
hydrolysis of epoxide 68 yielded a product with an 1H NMR identical with that of
commercial 2-naphthol.
Following a procedure similar to that outlined above, products from the
pH-independent reaction of 61 and 68 at pH 7.2 (2×10-3 M MOPSO) (stirred for 15 min)
were isolated and analyzed by 1H NMR. The spectrum of the product from reaction of 61
was identical to that of 1-naphthol and the NMR spectrum of the product from reaction of
68 was identical to that of 2-naphthol.
In semi-preparative scale reactions of the hydrolysis of the deuterium substituted
1-deuterio-7-methoxynaphthalene 1,2-oxide 61-1d, 1.0 mL of the stock solution of 61-1d
in acetone-d6 (~ 5 mg/mL) was added to a series of vigorously stirred aqueous solutions
(5 mL) with different pHs. The aqueous solution was then extracted twice with 10 mL
diethyl ether. The combined ether layers were dried over Na2SO4. After removal of
solvent, NMR spectra were taken on the residues.
From the NMR spectrum of 1-naphthol, the C-2 hydrogen has a chemical shift of
δ 6.80. By comparing the integral of this signal left in the NMR spectra of products with
the area of absorption due to the other five aromatic hydrogens that are at δ (7.71 – 7.14),
the fraction of deuterium remaining on C-2 can be calculated. The results are summarized
in Table 16. The data are plotted in Figure 11. Plots of deuterium retention vs. pH are
shown in Figure 12.
- 72 -
Table 16. The deuterium located on C-2 in 1-naphthol formed for the
reactions of 61-1d
Isomerization Condition
pH 1.05
pH 2.05
pH 2.84
pH 3.15
pH 4.58
pH 7.76 ( EPPS 0.002 M)
pH 12.5 a
% Deuterium Remaining in 1-Naphthol
17
18
31
41
79
83
81
a
The product was collected by extraction of the acidified reaction mixture. The
possibility of proton exchange of was excluded by the fact that the percentage of
deuterium remained the same regardless of reaction time.
Deuterium Retention %
Figure 12. Plot of deuterium retention vs pH
1.00
0.00
0.75
0.25
0.50
0.50
0.25
0.75
0.00
0
2
4
6
8
pH
- 73 -
10
12
14
1.00
B. Discussion
1. Mechanisms of the Acid-catalyzed Hydrolysis of 61
a. Substituent Effects on Acid-catalyzed Hydrolysis of 61
In acidic solutions, epoxides react with H3O+ to give a carbocation in rate limiting
steps if the positive charge in the intermediate carbocation can be stabilized by adjacent
groups. If the carbocation is not sufficiently stabilized to be an intermediate, the rate
limiting step may be the neucleophilic attack of solvent on the protonated epoxide. In
both of these mechanisms, there is substantial positive charge developed at the transition
state. For example, the rates of acid-catalyzed hydrolysis and methanolysis of substituted
styrene oxides give good Hammet-correlation, yielding a ρ+ value for hydrolysis of -4.230
and ρ+ value for methanolysis of -4.1.31 Therefore, positive charge in the transition state
for acid-catalyzed hydrolysis of styrene oxides is stabilized by electron-donating groups,
resulting in dramatically increased rates. For example, 4-methoxystyrene oxide reacts
over 400 times faster than styrene oxide in the acid-catalyzed hydrolysis,30 while
6-methoxy-1,2,3,4-tetrahydronaphthalene 1,2-oxide reacts 336 times faster than the
non-substituted 1,2,3,4-tetrahydronaphthalene 1,2-oxide in this acid-catalyzed reaction.58
The rates for the acid-catalyzed hydrolysis and pH-independent reaction of
7-methoxynaphthalene 1,2-oxide (61) and unsubstituted naphthalene 1,2-oxide (75) were
determined in 50:50 dioxane/water at the 25 °C. Epoxide 61 reacts 20 times faster than 75
in the acid-catalyzed hydrolysis, but 1400 times faster than 75 in the pH-independent
- 74 -
reaction. Therefore, compared with the substituent effects of the methoxy group on the
acid-catalyzed hydrolysis of styrene oxide and 1,2,3,4-tetrahydronaphthalene 1,2-epoxide,
it is amazing to find that for 7-methoxynaphthalene 1,2-oxide (61), the substituent effect
of a 7-methoxy group is very small. The only explaination for this very small substituent
effect is that there is not a significant positive charge developed at the C-2 carbon in the
transition state. In another words, the transition state for the acid-catalyzed hydrolysis of
61 is “early”, where the geometry of the transition state is close to that of reactant.
Scheme 17.
H
O
H3CO
H3CO
OH
H
OH
H3CO
H3O+
61
76
77
b. Kinetic Deuterium Isotope Effects on the Acid-catalyzed Hydrolysis of 61-1d
A possible mechanism for the acid-catalyzed hydrolysis of 61-1d is shown in
Scheme 18. The kinetic deuterium isotope effect (kH/kD) for this reaction was determined
to be 0.96 ± 0.01, which is consistent with a mechanism in which carbocation formation
is the rate-limiting step. This isotope effect is very different from that reported for the
acid-catalyzed hydrolysis of naphthalene 1,2-oxide-1d (kH/kD = 1.05).71
- 75 -
Scheme 18.
H3CO
D O
D OH
H3CO
H+
OH
H ~ H H3CO
H
D
r.d.s.
-H+
H
76-1d
61-1d
O
H3CO
H
D
+
77-2d
OH
H3CO
78-2d
H3CO
H
79
OH
D
79-2d
The kinetic deuterium isotope effects on the acid-catalyzed reaction of 61-1d and
of naphthalene 1,2-oxide-1d are both slightly “inverse”. These isotope effects are clearly
different than the isotope effect on the acid-catalyzed hydrolysis of 6-methoxy-1, 2, 3,
4-tetrahydronaphthalene 1, 2-epoxide-2d 80 (Scheme 20), which was determined to be
significantly inverse ( kH/kD = 0.93 ± 0.01 ).72 This inverse kinetic isotope effect in the
Scheme 19.
O
OH
D
H3CO
+
H
r.d.s.
D
H2O
Diols
H3CO
80
81
acid-catalyzed hydrolysis of 80 was attributed to a change in hybridization at C-2 carbon
from sp2-like in the reactant to sp3 in the intermediate carbocation 81. The experimental
isotope effect for the acid-catalyzed hydrolysis of 61-1d is still inverse, but it is closer to
unity. A possible explanation of this isotope effect in the acid-catalyzed reaction of 61-1d
is that the transition state for the reaction of 61-1d is early such that rehybridization at
- 76 -
C-1 carbon is not very far advanced. The inductive effect of deuterium and some level of
rehybridization of C-1 carbon together account for this isotope effect on the reaction of
61-1d. An ”early” transition state for the acid-catalyzed hydrolysis reaction of 61-1d with
some level of rehybridization of C-1 carbon is supported by the relative small but existing
substituent effect of the methoxy group.
2. Mechanisms of the pH-Independent Reaction of 61
a. Substituent Effects of pH-Independent Reaction of 61
In 50:50 dioxane/water at 25 ℃ with 0.1 M NaClO4, epoxide 61 reacts 1400 times
faster then 75 in the pH-independent reaction. The methoxy group therefore has a very
large substituent effect on the pH-independent reaction. This result indicates that in the
pH-independent reaction of 61, there is significant positive charge developed on C-2 as
shown in Scheme 21. In the transition state, the O-C2 bond breaking must be relatively
advanced.
b. Kinetic Deuterium Isotope Effects on the pH-Independent Reaction of 61
The kinetic deuterium isotope effect for the pH-independent reaction of
naphthalene oxide (k0(75)/k0(75-1d) = 1.08 ± 0.01) is very similar to that for the
pH-independent reaction of 7-methoxynaphthalene 1,2-oxide (k0(61)/k0(61-1d) = 1.09 ±
0.01). Our measured kinetic isotope effect on the pH-independent reaction of naphthalene
oxide (75 vs. 75-1d) is somewhat larger than that reported by Bruce (1.05).71 The
observed isotope effects are much smaller than what is expected for a primary isotope
effect. Based on the small kinetic deuterium isotope effect for the reaction of 75,
- 77 -
rate-limiting epoxide ring opening to form zwitterion 82 was proposed in Scheme 22.71 In
this mechanism, deuterium migration occurs after the rate determining step, and a
primary kinetic isotope effect on this step will not be reflected in the observed isotope
effect.
Scheme 20.
D
O
O
D
H3CO
r.d.s
61-1d
H3CO
O
fast
OH
D
H3CO
H(D)
H3CO
H
78
82
79 or 79-2d
The kinetic isotope effect on the pH-independent reaction of 61-1d is much
smaller than the isotope effects observed for the pH-independent reaction of
6-methoxy-1,2,3,4-tetrahydronaphthalene 1,2-epoxide (80) (k0(H)/k0(D)) = 1.59)38 and
5-methoxyindene 1,2-oxide (23) ((k0(H)/k0(D) =2.22)38, 72 For the pH-independent reaction
of both epoxides above, rate-limiting hydrogen migration was proposed.
The possible mechanisms for the pH-independent reaction of 61-1d are outlined
in Scheme 21. One mechanism similar to that proposed for reaction of naphthalene
1,2-oxide involves rate-limting epoxide ring opening to form a zwitterion intermediate 82,
which leads to phenol product 79 and 79-d via ketone 78-2d. A second possible
mechanism is the concerted rearrangement of 61-1d to ketone 78-2d (path b). The large
substituent effect of the methoxy group indicates that the epoxide C-O bond is
substantially broken at the transition state. A relatively small kinetic deuterium isotope
- 78 -
effect for the reaction of 61-1d indicates that deuterium atom migration is not far
advanced.
Scheme 21.
path a
H3CO
O
D O
OH
D
H
H3CO
H
H3CO
r.d.s.
D
H3CO
82
78-2d
79
O
O
61-1d
path b
H3CO
OH
D
H
D
H3CO
r.d.s.
79-2d
83
This type of concerted reaction in which C-O bond breaking is advanced but
hydrogen migrate is not advanced has been referred as “ an asynchronous concerted”
reaction.73 High level quantum chemical calculations on the rearrangement of protonated
propylene oxide in the gas phase to the conjugate acid of propanal indicate that the C-O
bond is completely broken at the transition state before hydrogen migration occurs, yet
the reaction is concerted. (Scheme 22).
Scheme 22.
H
O
H
H
H
H3C
H3C
H
H
O
H
O
H
H3C
H
If the reaction of 61-1d involves rate-limiting epoxide C-O bond breaking to form
zwitterion 82, then the deuterium isotope is expected to be inverse as in the
- 79 -
acid-catalyzed hydrolysis of 61-1d (Scheme 19) to reflect change of hybridization at C-1.
The fact that it is a little larger than unity (1.09) suggests some deuterium migration at the
transition state.
In summary, an asynchronous concerted mechanism for the pH-independent
reaction of 61-1d is somewhat more consistent with the observed kinetic isotope effect
than the stepwise mechanism (path a), although path a cannot be ruled out.
3. Solvent Isotope Effect on the Hydrolysis Reaction of 61
There is a substantially inverse solvent isotope effect on the acid-catalyzed
hydrolysis of 61 (( kH (H2O) / kH (D2O) ) ≈ 0.57). This isotope effect is consistent with the
mechanism proposed in Scheme 19 in which epoxide 61 reacts with H+ to form
carbocation 76 in a rate-limiting step. The rate for the acid-catalyzed hydrolysis of 61 in
50:50 D2O/Dioxane is faster than in H2O/Dioxane because D3O+ in D2O is a “stronger
acid” than H3O+ in H2O. In comparison, kH (H2O) / kH (D2O) for acid-catalyzed
hydrolysis of a benzo[a]pyrene 7,8-diol-9,10-epoxide is 0.67.74
The small normal solvent isotope effect on the pH-independent reaction of 61 (k0
(H2O) / k0 (D2O) ≈ 1.16 ) indicates very little proton transfer from solvent at the transition
state, and this rules out a mechanism in which D2O acts as a general acid to form a
carbocation intermediate. The solvent isotope effect on the pH-independent reaction of a
- 80 -
a benzo[a]pyrene diol epoxide was observed to be 2.6, and a carbocation intermediate
was trapped by nucleophilic reagents.74
4. Solvent Effect on the Acid-catalyzed and pH-Independent Reaction of 61
The bimolecular rate constant of the acid-catalyzed hydrolysis of 61 in 30:70
dioxane/water is approximately 3 times larger than that in 50:50 dioxane/water. The kH
value for reaction of 61 is not highly accurate because insufficient rate data could be
collected in the pH region when acid-catalyzed hydrolysis is the major reaction. In a
study of the solvent effect on hydrolysis of 5-methoxyindene oxide, the solvent change
from 25:75 dioxane/water to pure water increases the rate for its acid-catalyzed
hydrolysis by only 14%. A solvent change from 30:70 dioxane/water to 10:90
dioxane/water increases the rate of the acid-catalyzed hydrolysis of
6-methoxy-trans-1,2,3,4,4a,10a-hexahydro-phenanthrene 9,10-oxide by a factor of only
1.6.75 Our observation of a relatively small solvent effect on the acid-catalyzed hydrolysis
of 61 is consistent with what has been published.
The pH-independent reaction of 61 in water is too fast to be measured by simple
mixing technique. It is known that decreasing the percentage of dioxane in the
dioxane-water solvent will significantly increase the rate of pH-independent reaction of
aryl epoxide, because the transition state with charge developed at the benzylic position
can be stabilized better in more polar solvent. For example, the rate of the
- 81 -
pH-independent reaction of 5-methoxyindene oxide is 5.8 times faster in water than in
25:75 dioxane/water.75 We observed that the rate for the pH-independent reaction of 61 is
about 9 times faster in 30:70 dioxane/water than in 50:50 dioxane/water.
5. Product Study of the Acid-catalyzed and pH-Independent Reactions of 61-1d
The lack of large kinetic isotope effects in the acid-catalyzed and pH-independent
reaction of 61 indicates that epoxide C-O bond breaking is the rate-limiting step for both
reactions. From pH 2-4, the deuterium retention on the C-2 carbon in the product from
reaction of 61-1d changes dramatically from 20% - 80%, which indicates that the
acid-catalyzed hydrolysis and pH-independent reaction proceed via quite different
pathways after the rate-limiting step.
Scheme 25.
+
H
D OH
H3CO
OH
H ~H
H3CO
-H+
H
D
H
76-1d
77-2d
H3CO
78-2d
OH
OH
H3CO
H
D
+
r.d.s.
D
O
H3CO
H3CO
H
D
O
79
79-2d
61-1d
r.d.s.
H3CO
path a
O
D O
82
OH
H3CO
path b
D
H
H
H3CO
78-2d
O
r.d.s.
D
H
H3CO
79
OH
D
H3CO
79-2d
83
- 82 -
It has been observed that the pH-independent reaction of naphthalene
1,2-oxide-1d yielded phenol with 80% of the original deuterium remaining on C-2.
37
It
was proposed that all of the deuterium migrate from C1-C2, and that there is a deuterium
isotope effect of 4.0 in the product-forming step. The deuterium retention in 79 from the
pH-independent reaction of 61-1d is also 80%, which suggests that all of the product is
derived from 78-2d, form by ether path a or path b (Scheme 25).
In the acid-catalyzed hydrolysis of 61-1d, the hydroxyl carbocation 76-1d
+
(Scheme 23) can either undergo direct “loss” of D to give the product 79 or undergo
deuteride migration to give 78-2d via 77-2d, which then isomerizes to give 79 and 79-2d.
The product 79-2d is only generated from deprotonation of 78-2d. Due to a deuterium
isotope effect, hydrogen is lost faster than deuterium in deprotonation. If all the
deuterium from 76-1d migrates to give 78-2d via 77-2d, a much higher deuterium
retention is expected that if D+ is lost directly from 76-1d.
The deuterium retention in 79, formed from the acid-catalyzed pathway, is only
20%, and therefore a significant fraction of 76-1d reacts by direct loss of D+. If it is
assumed that the deuterium isotope effect on the product-forming step of this reaction is
also 4.0, then it is calculated that 75% of 76-1d undergoes directed loss of D+ and only
25% undergoes deuterium migration. If it is further assumed that the deuterium isotope
effect for direct loss of D+ from carbocation 78-2d is 4.0 and the isotope effect for
- 83 -
deuterium migration is 2.0 (non-linear transition state), then it is estimated that about
86% of H+ is lost directly from 76 and only 14 % undergoes hydrogen migration.
C. Conclusion
In this study of the hydrolysis reactions of naphthalene 1,2-oxide 75, the methoxy
substituted naphthalene 1,2-oxide 61, and their 1-deuterio derivatives 75-1d and 61-1d, it
is concluded that epoxide ring-opening is the rate-limiting step in both the acid-catalyzed
hydrolysis and pH-independent reaction of naphthalene oxides 75 and 61. However, in
the acid-catalyzed hydrolysis of 75 and 61, the kinetic deuterium isotope effects are
slightly “inverse”, which is attributed to “early” transition states in which the C-O bond
breaking is not very advanced in the transition state. This conclusion is also supported by
the very small substituent effect for the acid-catalyzed hydrolysis of 75. In the
pH-independent reactions of 75 and 61, an asynchronous concerted mechanism for the
pH-independent reaction of 71 and 61 is somewhat more consistent with the kinetic
isotope effect than the stepwise mechanism.
The phenol product from the acid-catalyzed hydrolysis of 61-1d contains only
20% of the original deuterium, whereas the phenol product from the pH-independent
reaction of 61-1d contains 80% of the original deuterium. In the acid-catalyzed reaction
(pH < 2) of 61, most of the intermediate carbocation 76 undergoes direct loss of a proton
from the C-1 carbon of 76 rather than undergo hydride migration from C-1 to C-2. In the
- 84 -
pH-independent reaction (pH >4), Most of all of the hydrogens on C-1 carbon migrate to
C-2.
D. Experimental Procedures
1. Materials and Methods. Dioxane and THF were distilled from sodium prior to use.
All other reagents were purchased from commercial sources. Quantum chemical
calculations were performed with the molecular modeling program Spartan04
(Wavefunction, Inc.). The pH values given throughout are those measured by the glass
electrode, and for aqueous dioxane, they correspond to apparent pH values. The activity
of hydronium ion measured by the glass electrode was assumed to be equal to the
concentration of hydronium ion.
2. Synthesis
7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-ol (56).64 To a stirred mixture of lithium
aluminum hydride (0.93 g, 24.4 mmol) in 20 mL of stirred anhydrous diethyl ether was
slowly added 7-methoxy-1-tetralone (8.60 g, 48.8 mmol). The mixture was stirred under
reflux for 1 h after all the ketone was added. The reaction mixture was neutralized with 3
N H2SO4 solution, and extracted with 50 mL ether twice. The combined organic phases
were dried over Na2SO4 and filtered. Removal of solvent under vacuum afforded 8.6 g of
slightly yellow oil. This material was used in the next step without further purification.
1
H NMR (CDCl3, 400 MHz): δ 7.01 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 2.8 Hz, 2H), 6.79
- 85 -
(dd, J1 = 2.8 Hz, J2 = 8.2 Hz, 1H), 4.72 (apparent t, 1H), 3.79 (s, 3H), 2.85-2.62 (m, 2H),
2.11-1.70 (m, 4H).
7-Methoxy-1,2,-dihydronaphthalene (57).65 Alcohol 56 (5.0 g, 28.2 mmol) and
para-toluenesulfonic acid monohydrate (0.3 g, 1.6 mmol ) in 90 mL toluene were brought
to boil and refluxed for half an hour in a Dean-Stark apparatus. The reaction mixture was
allowed to cool down and washed twice with 30 mL saturated Na2CO3. The toluene layer
was dried over Na2SO4. Removal of solvent under vacuum gave 4.45 g of yellow oil
(98.6% yield), which was further distilled at 60 °C at 0.02 mm Hg to afford colorless
olefin (3.67 g). 1H NMR (CDCl3, 400 MHz): δ 7.00 (d, J = 8.2 Hz, 1H), 6.66 (dd, J1 = 2.3,
J1= 8.2 Hz, 2H), 6.60 (d, J = 2.3 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H), 6.04 (m, 1H), 3.78 (s,
3H), 2.93-2.80 (m, 2H), 2.51 (d, 1H), 2.51-2.45 (m, 1H), 2.29-2.21 (m, 1H).
2-Bromo-7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ol (58).66, 67
6-Methoxy-1,2-dihydronaphthalene (6.33g, 39.5mmol) and N-bromoacetamide (5.45g,
39.5 mmol) were stirred in 200 mL 3:1 THF/water for 3 h. The solution was concentrated
under vacuum to remove most of the THF and extracted with 50 mL ethyl acetate twice.
The organic layer was dried over calcium sulfate, filtered, and removal of the solvent
afforded 9.87 g slightly yellow solid (yield 97.7%). Recrystallization of the solid product
from ethyl acetate/diethyl ether 1:1 afforded 5.78 g of white crystals. mp. 89-90°C (mp
lit.76 89-90 °C). 1H NMR (CDCl3, 400 MHz): δ 7.05 (d, J = 2.8 Hz, 1H), 7.00 (d, J = 8.7
Hz, 1H), 6.80 (dd, J1 = 2.3 Hz, J1= 8.7 Hz, 1H), 4.86 (m, 1H), 4.34 (m, 1H), 3.80 (s, 3H),
2.72 (t, 2H), 2.33-2.26 (m, 2H).
- 86 -
1-Tifluoroacetoxy-2-bromo-7-methoxy-1,2,3,4-tetrahydronaphthalene (59). To a
solution of bromohydrin (4.11 g, 16.0 mmol) in 10 mL chloroform was added dropwise
trifluoroacetic anhydride (5.56 g, 26.5 mmol) in 15 mL chloroform. The reaction solution
was stirred in an ice-bath for 1 h and concentrated under vacuum. Dry diethyl ether (100
mL) and anhydrous K2CO3 (10 g, 100 mmol) were added, and the mixture was stirred for
another 2 h. Solid salt was filtered out and solvent was removed to give 5.23 g brown oil
( 92.7%) which was slowly solidified in the refrigerator. The crude product was
chromatographed to give 4.1 g of white solid. m.p. 55-56 °C. 1H NMR (CDCl3, 400
MHz): δ 7.11 (d, J = 8.6 Hz, 1H), 6.90 (dd, J1 = 2.7 Hz, J1= 8.6 Hz, 1H), 6.75 (d, J =
2.7 Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 4.50 (m, 1H), 3.78 (s, 3H), 3.05-2.97 (m, 1H),
2.91-2.83 (m, 3H), 2.50-2.42 (m,1H), 2.29-2.21 (m, 1H). Anal. calcd for C13H12BrF3O3:
C, 44.22; H, 3.43. Found: C, 44.07; H, 3.42
1-Tifluoroacetoxy-2, 4-dibromo-7-methoxy-1,2,3,4-tetrahydronaphthalene (60).
A mixture of N-bromosuccinimide (0.604 g, 3.40 mmol), catalytic amount of AIBN (10
mg) and the solution of monobromide 59 (1.09 g, 3.1 mmol) in 20 mL carbon
tetrachloride was heated at 55 – 65 °C for 15 min under N2. The mixture was then
irradiated with a sun lamp for 45 min. The solid succinimide was filtered out and the
organic layer was concentrated under vacuum to yield 1.16 g brown oil (87.2%) which
slowly solidified at room temperature. The solid was dissolved in ether and recrystallized
to give 0.51 colorless crystals that decompose at 85 °C. 1H NMR (CDCl3, 400 MHz): δ
7.39 (d, J = 8.6 Hz, 1H,), 6.93 (dd, J1 = 2.3 Hz, J1= 8.6 Hz, 1H), 6.55 (d, J = 2.8 Hz, 2H),
- 87 -
6.41 (d, J = 8.2 Hz, 1H), 5.52 (t, 1H), 4.83 (m, 1H), 3.79 (s, 3H), 2.97 (m,1H), 2.79 (m,
1H). This material is too light sensitive and unstable at room temperature to be sent for
analysis, and therefore it was used immediatlely in the next step..
7-Methoxynapthalene 1,2-oxide (61). A mixture of anhydrous sodium methoxide (108
mg, 2.0 mmol) in 3 mL anhydrous fresh THF was stirred and cooled in ice-bath. A
solution of dibromide 63 (108 mg, 0.25 mmol) in 2 mL of dry THF was added dropwise
through a syringe. The mixture was stirred at an ice bath for a day. Most of the solvent
was removed under vacuum at 0 °C. Fresh pentane (5 mL) was added to the residual
white solid, and the pentane solution was washed twice with 3 mL of water, 3 mL of 1.0
M NaOH, and dried over sodium sulfate. The solvent was removed with a gentle stream
of N2 to give 25.5 mg white solid (58.6%). 1H NMR (CDCl3, 400 MHz): δ 7.31-7.28
(2H), 6.96 (dd, J1 = 2.7 Hz, J1= 8.6 Hz, 1H), 6.73 (dd, J1 = 1.4 Hz, J1= 9.6 Hz, 1H), 6.27
(dd, J1 = 4.1 Hz, J = 9.6 Hz, 1H), 4.43 (d, J = 3.6 Hz, 1H), 4.06-4.04 (m, 1H), 3.87 (s,
3H). HRMS (FAB) Calcd for C11H10O2 174.0678, found 174.0678.
6-Methoxy-1,2,-dihydronaphthalene (64).77
6-Methoxy-1,2,3,4-tetrahydronaphthalene-1-ol
63
(5.0
g,
28.2
mmol)
and
para-toluenesulfonic acid monohydrate (0.3 g, 1.6 mmol ) in 90 mL toluene were brought
to boil and refluxed for half an hour in a Dean-Stark apparatus. The reaction mixture was
allowed to cool down and was then washed twice with saturated Na2CO3 (30 mL). The
toluene layer was dried over Na2SO4. Removal of solvent under vacuum gave 4.45 g of
- 88 -
yellow oil (98.6% yield), which was further distilled at 60 °C under 0.02 mmHg to afford
colorless olefin (3.67 g). 1H NMR (CDCl3, 400 MHz): δ 6.93 (d, J = 9.1 Hz, 1H),
6.73-6.67 (2H), 6.41 (d, J = 9.6 Hz, 2H), 5.89 (m, 1H), 3.79 (s, 3H), 2.78-2.74 (m, 2H),
2.31-2.25 (m, 2H).
2-Bromo-6-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ol (65).58
6-Methoxy-1,2-dihydronaphthalene (6.33g, 39.5mmol) and N-bromoacetimide (5.45 g,
39.5 mmol) were stirred in 200 mL 3:1 THF/Water for 3 h. The solution was
concentrated under vacuum to remove most of the THF, and the mixture was then
extracted with 50 mL ethyl acetate twice. The organic layer was dried over calcium
sulfate and filtered. Removal of the solvent afforded 9.87 g slightly yellow solid (yield
97.7%). Recrystallization of the solid product from ethyl acetate/diethyl ether 1:1
afforded 5.78 g of white crystals. mp 78-79 °C (m.p. lit
78
80-81°C) 1H NMR (CDCl3,
400 MHz): δ 7.41 (d, J = 8.7 Hz, 1H), 6.80 (dd, J1 = 2.8 Hz, J1= 8.7 Hz, 1H), 6.62 (d, J =
2.7 Hz, 1H), 4.87 (dd, J1 = 3.2 Hz, J1= 6.0 Hz, 1H), 4.35 (m, 1H), 3.79 (s, 1H), 3.00-2.84
(m, 2H), 2.53-2.46 (m, 1H), 2.40 (d, 1H), 2.29-2.23 (m, 1H).
1-Acetoxy-2-bromo-6-methoxy-1,2,3,4-tetrahydro-naphthalene (66). To a ice cooled
solution of bromohydrin 65 (1.3 g, 5.06 mmol) and triethylamine (3.07 g, 30.3 mmol) in
20 mL chloroform was added dropwise acetyl chloride (1.20 g, 15.2 mmol) in 10 mL
chloroform. The resulting solution was heated under reflux for 8 h, cooled and washed
with water 30 mL twice. The organic layer was dried over sodium sulfate. Removal of
solvent under low pressure (0.5 mm Hg) gave thick oil, 1.46 g (96.8%). The oil product
- 89 -
was chromatographed through silica gel to give 1.21 g white solid. mp. 96-97 °C 1H
NMR (CDCl3, 400 MHz): δ 7.19 (d, J = 8.7 Hz, 1H), 6.77 (dd, J1 = 2.7 Hz, J1= 8.7 Hz,
1H), 6.67 (d, 1H, J = 2.7 Hz), 4.48 (m, 1H), 3.79 (s, 3H), 3.09-3.03 (m, 2H), 2.87-2.83
(m, 1H), 2.44-2.42 (m, 1H), 2.21-2.17 (m, 1H), 2.08 (s, 3H). Anal. calcd for C13H15BrO3:
C, 52.19; H, 5.05. Found: C, 51.98; H, 5.02
1-Acetoxy-2,4-bromo-6-methoxy-1,2,3,4-tetrahydro-naphthalene (67). A mixture of
N-bromosuccinimide (0.215 g, 1.207 mmol), catalytic amount of AIBN (10 mg) and
momnobromide 66 (1.09 g, 3.1 mmol) in 10 mL carbontetrachloride was heated at 55 –
65 °C for 15 min under N2. The mixture was then irradiated with a sun lamp for 20 min.
The solid succinimide was filtered out and the organic layer was concentrated under
vacuum to yield 0.51 g crude oily product. Column chromatography through deactivated
alumina followed by a recrystallization in 1:3 ether/pentane afforded 97 mg white
crystals (yield 22%), mp 104 °C. This material decomposes upon standing at rt overnight,
and therefore it was not sent out for analysis. The product was used immediately in the
next step. 1H NMR (CDCl3, 400 MHz): δ 7.09 (d, J = 8.7 Hz, 1H), 6.95 (d, J1 = 2.7 Hz,
1H), 6.86 (d, J1 = 2.7 Hz, J2 = 8.7 Hz, 1H) 5.47 (apparent t, 1H), 3.81 (s, 3H), 2.98-2.96
(m, 2H), 2.81-2.74 (m, 1H), 2.19 (s, 3H).
6-Methoxynapthalene 1,2-oxide (68). A mixture of anhydrous sodium methoxide (108
mg, 2.0 mmol) in 3 mL anhydrous fresh THF was stirred and cooled in ice-bath. A
solution of dibromide (100 mg, 0.23 mmol) in 3 mL of anhydrous fresh THF was
dropwise added through a syringe. The mixture was stirred in an ice-bath for a day. Most
- 90 -
of the solvent was removed under vacuum at 0 °C. Fresh pentane 5 mL was added to the
residual white solid and the pentane solution was washed twice by 3 mL of water, twice
with 3 mL 1.0 M NaOH and dried over sodium sulfate. The solvent was removed with a
gentle stream of N2 to give 20.1 mg white solid (50.0%). 1H NMR (CDCl3, 400 MHz): δ
7.58 (d, J = 8.2 Hz, 1H), 6.95-6.92 (2H), 6.75 (dd, J1 = 1.4 Hz, J2= 9.6 Hz, 1H), 6.45 (dd,
J1 = 4.1 Hz, J2 = 9.6 Hz, 1Hz), 4.43 (d, J = 4.1 Hz, 1H), 4.04 (m, 1H), 3.83 (s, 3H).
HRMS (FAB) Calcd for C11H10O2 174.0678, found 174.0665.
- 91 -
H
OH
H3CO
H NMR (CDCl3, 400 MHz): δ 7.01 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 2.8 Hz, 2H), 6.79 (dd, J1 = 2.8 Hz, J2 = 8.2
Hz, H), 4.72 (apparent t, 1H), 3.79 (s, 3H), 2.85-2.62 (m, 2H), 2.11-1.70 (m, 4H).
1
- 92 -
D
OH
H3CO
H NMR (CDCl3, 400 MHz): δ 7.01 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 2.8 Hz, 2H), 6.79 (dd, J1 = 2.8 Hz, J2 = 8.2
Hz, H), 3.79 (s, 3H), 2.85-2.62 (m, 2H), 2.11-1.70 (m, 4H).
1
- 93 -
H
H3CO
H NMR (CDCl3, 400 MHz): δ 7.00 (d, J = 8.2 Hz, 1H), 6.66 (dd, J1 = 2.3, J1= 8.2 Hz ,2H), 6.60 (d, J = 2.3 Hz, 1H),
6.42 (d, J = 9.6 Hz, 1H), 6.04 (m, 1H), 3.78 (s, 3H), 2.93-2.80 (m, 2H), 2.51 (d, 1H), 2.51-2.45 (m, 1H), 2.29-2.21 (m,
1H).
1
- 94 -
D
H3CO
H NMR (CDCl3, 400 MHz): δ 7.00 (d, J = 8.2 Hz, 1H), 6.66 (dd, J1 = 2.3, J1= 8.2 Hz ,2H), 6.60 (d, J = 2.3 Hz,
1H), 6.04 (m, 1H), 3.78 (s, 3H), 2.93-2.80 (m, 2H), 2.51 (d, 1H), 2.51-2.45 (m, 1H), 2.29-2.21 (m, 1H).
1
- 95 -
H
H3CO
OH
Br
H NMR (CDCl3, 400 MHz): δ 7.05 (d, J = 2.8 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.80 (dd, J1 = 2.3 Hz, J1= 8.7
Hz, 1H), 4.86 (m, 1H), 4.34 (m, 1H), 3.80 (s, 3H), 2.72 (t, 2H), 2.33-2.26 (m, 2H).
1
- 96 -
D
H3CO
OH
Br
H NMR (CDCl3, 400 MHz): δ 7.05 (d, J = 2.8 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.80 (dd, J1 = 2.3 Hz, J1= 8.7
Hz, 1H), 4.34 (m, 1H), 3.80 (s, 3H), 2.72 (t, 2H), 2.33-2.26 (m, 2H).
1
- 97 -
H
H3CO
OCOCF3
Br
H NMR (CDCl3, 400 MHz): δ 7.11 (d, J = 8.6 Hz, 1H), 6.90 (dd, J1 = 2.7 Hz, J1= 8.6 Hz, 1H), 6.75 (d, J = 2.7
Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 4.50 (m, 1H), 3.78 (s, 3H), 3.05-2.97 (m, 1H), 2.91-2.83 (m, 3H), 2.50-2.42
(m,1H), 2.29-2.21 (m, 1H).
1
- 98 -
D
H3CO
OCOCF3
Br
H NMR (CDCl3, 400 MHz): δ 7.11 (d, J = 8.6 Hz, 1H), 6.90 (dd, J1 = 2.7 Hz, J1= 8.6 Hz, 1H), 6.75 (d, J = 2.7
Hz, 1H), 4.50 (m, 1H), 3.78 (s, 3H), 3.05-2.97 (m, 1H), 2.91-2.83 (m, 3H), 2.50-2.42 (m,1H), 2.29-2.21 (m, 1H).
1
- 99 -
H
OCOCF3
H3CO
Br
Br
H NMR (CDCl3, 400 MHz): δ 7.39 (d, J = 8.6 Hz, 1H), 6.93 (dd, J1 = 2.3 Hz, J1= 8.6 Hz, 1H), 6.55 (d, J = 2.8
Hz, 2H), 6.41 (d, J = 8.2 Hz, 1H), 5.52 (t, 1H), 4.83 (m, 1H), 3.79 (s, 3H), 2.97 (m,1H), 2.79 (m, 1H).
1
- 100 -
D
OCOCF3
H3CO
Br
Br
H NMR (CDCl3, 400 MHz): δ 7.39 (d, J = 8.6 Hz, 1H), 6.93 (dd, J1 = 2.3 Hz, J1= 8.6 Hz, 1H), 6.55 (d, J = 2.8 Hz,
2H), 6.41 (d, J = 8.2 Hz, 1H), 5.52 (t, 1H), 4.83 (m, 1H), 3.79 (s, 3H), 2.97 (m,1H), 2.79 (m, 1H).
1
- 101 -
H
O
H3CO
H NMR (CDCl3, 400 MHz): δ 7.31-7.28 (2H), 6.96 (dd, J1 = 2.7 Hz, J1= 8.6 Hz, 1H), 6.73 (dd, J1 = 1.4 Hz, J1= 9.6
Hz, 1H), 6.27 (dd, J1 = 4.1 Hz, J = 9.6 Hz, 1H), 4.43 (d, J = 3.6 Hz, 1H), 4.06-4.04 (m, 1H), 3.87 (s, 3H).
1
- 102 -
D
O
H3CO
H NMR (CDCl3, 400 MHz): δ 7.31-7.28 (2H), 6.96 (dd, J1 = 2.7 Hz, J1= 8.6 Hz, 1H), 6.73 (dd, J1 = 1.4 Hz, J1= 9.6
Hz, 1H), 6.27 (dd, J1 = 4.1 Hz, J = 9.6 Hz, 1H), 4.06-4.04 (m, 1H), 3.87 (s, 3H).
1
- 103 -
H3CO
H NMR (CDCl3, 400 MHz): δ 6.93 (d, J = 9.1 Hz, 1H), 6.73-6.67 (2H), 6.41 (d, J = 9.6 Hz, 2H), 5.89 (m, 1H), 3.79
(s, 3H), 2.78-2.74 (m, 2H), 2.31-2.25 (m, 2H).
1
- 104 -
OH
Br
H3CO
H NMR (CDCl3, 400 MHz): δ 7.41 (d, J = 8.7 Hz, 1H), 6.80 (dd, J1 = 2.8 Hz, J1= 8.7 Hz, 1H), 6.62 (d, J = 2.7
Hz, 1H), 4.87 (dd, J1 = 3.2 Hz, J1= 6.0 Hz, 1H), 4.35 (m, 1H), 3.79 (s, 1H), 3.00-2.84 (m, 2H), 2.53-2.46 (m, 1H),
2.40 (d, 1H), 2.29-2.23 (m, 1H).
1
- 105 -
OAc
Br
H3CO
H NMR (CDCl3, 400 MHz): δ 7.19 (d, J = 8.7 Hz, 1H), 6.77 (dd, J1 = 2.7 Hz, J1= 8.7 Hz, 1H), 6.67 (d, J = 2.7
Hz, 1H), 4.48 (m, 1H), 3.79 (s, 3H), 3.09-3.03 (m, 2H), 2.87-2.83 (m, 1H), 2.44-2.42 (m, 1H), 2.21-2.17 (m,
1H), 2.08 (s, 3H).
1
- 106 -
OAc
Br
H3CO
Br
H NMR (CDCl3, 400 MHz): δ 7.09 (d, J = 8.7 Hz, 1H), 6.95 (d, J1 = 2.7 Hz, 1H), 6.86 (d, J1 = 2.7 Hz, J2 =
8.7 Hz, 1H), 5.47 (apparent t, 1H), 3.81 (s, 3H), 2.98-2.96 (m, 2H), 2.81-2.74 (m, 1H), 2.19 (s, 3H).
1
- 107 -
H
O
H3CO
H NMR (CDCl3, 400 MHz): δ 7.09 (d, J = 8.7 Hz, 1H), 6.95 (d, J1 = 2.7 Hz, 1H), 6.86 (d, J1 = 2.7 Hz, J2 = 8.7
Hz, 1H), 5.47 (apparent t, 1H), 3.81 (s, 3H), 2.98-2.96 (m, 2H), 2.81-2.74 (m, 1H), 2.19 (s, 3H).
1
- 108 -
H
H3CO
HRMS (FAB) Calcd for C11H10O2 174.0678, found 174.0678.
- 109 -
O
H
H3CO
HRMS (FAB) Calcd for C11H10O2 174.0678, found 174.0665.
- 110 -
O
CHAPTER IV
Biphasic Epoxidation Mechanisms
- 111 -
A. Introduction to Mechanisms of Epoxidation by Peroxyacids
Epoxidation of olefins by peroxyacids, a general method in making epoxides, is
very important in organic synthesis.77, 79-81 Ever since the middle of last century, the
“butterfly” reaction mechanism proposed by Bartlett, in which peroxyacid delivers the
oxygen and accepts the proton. (Scheme 24), was thought to be the only mechanism for
this reaction.80 This model of the reaction mechanism is supported by several facts: 1) the
rate of the epoxidation is not significantly influenced by the polarity of solvent; 2) the ρ
value is only 0.8 for the epoxidation of trans-stilbene by series of peroxyacids.82 This low
ρ value indicates that the transition state of this reaction is “synchronous,” in another
Scheme 24. The classical mechanism of epxodiation of olefin by peroxyacid
R
O
O
O
R1
R2
R3
R4
R C
H
O
O
H
O
O
R1
R2
R3
R4
R1
R2
R3
R4
RCO2H
84
O
H
O
R C
O
H
O
O
R
C
O
R2
R1
R3
R4
85
words, not highly polarized.83 There is also another transition state model of a
synchronous nature proposed by Kwart and Hoffman – a 1,3-dipolar addition mechanism
- 112 -
with transition state 86.43 The reaction is observed to be stereospecific, i.e., cis alkenes
yield cis epoxides and trans alkenes yield trans epoxides.
As increasingly accurate computational methods
R
came into place, the classical mechanisms have been
O
O
H
O
challenged a lot. In case of the epoxidation of p-phenyl

H
styrene, there was a very small kinetic isotope effect
observed for the epoxidation of α-deuterated olefin, but a
H
H
Ar
86
somewhat larger kinetic isotope effect was observed for epoxidation of the β-deuterated
olefin. Based on this result, Hanzlik and co-workers proposed an “asynchronous”
transition state structure 86.44 In the transition state, extensive bond formation takes place
at the β carbon, while the α carbon remains sp2 hybridized. Partial charge at the α carbon
can be stabilized by phenyl group. Later on, Houk and co-workers proposed, through
high level quantum chemical calculations, that the bond lengths for both of the C-O bond
in the transition state for epoxidation of ethylene by peroxyacid are the same. This is a
typical picture of the “butterfly mechanism.” Upon substitution of H by a methoxy or
methyl group, the C-O bond of the more substituted carbon in the transition state will be
longer, which supports the Hanzlik theory.84
Epoxidation of olefins by peroxyacids is a most versatile method to prepare target
epoxides. In epoxidation of olefins, peroxyacids deliver an oxygen atom to the olefin and
a carboxylic acid, along with an epoxide, is formed. When the epoxide is sufficiently
- 113 -
reactive toward acidic reagents, however, the carboxylic acid formed as one of the
products of epoxidation reacts with the epoxide to form hydroxy esters. To prevent this
from happening, a procedure in which the reaction solution (usually CH 2Cl2) is stirred
with a water solution containing sodium bicarbonate85 or sodium phosphate86 was
developed. As the carboxylic acid is formed, it is extracted from the organic layer to the
water layer as the carboxylate ion. Under these biphasic conditions, many reactive
epoxides that do not survive the normal epoxidation procedures have been synthesized.
In the preparation of acid sensitive epoxides, biphasic epoxidation of the
precursor olefins with peroxyacids is often successful. It has been observed by our group
that
epoxidation
of
cis-β-methyl-4-methoxystyrene
(87)
with
MCPBA
in
dichloromethane-water with sodium carbonate solution gave both cis and trans epoxides
88 and 89 (Scheme 22).87 The mechanism of this epoxidation must be very different from
the well established concerted epoxidation mechanism, which would yield only cis
epoxide
88.
Scheme 24.
O
CH3
H3CO
CH3CO3H/CH2Cl2
O
CH3
CH3
Na2CO3
87
H3CO
- 114 -
88
H3CO
89
B. Result
1. Observations from Biphasic Epoxidation of Cis-stilbene
In order to further explore the mechanism of this non-stereospecific epoxidation,
epoxidation of cis-stilbene (90) was investigated. We expected to see a higher ratio of
trans product 92 because of the steric repulsion between two phenyl groups. The NMR
spectrum of the product showed that the biphasic epoxidation of cis-stilbene with sodium
bicarbonate, carbonate or phosphate yields mostly trans-stilbene oxide (92). Epoxidation
of cis-stilbene with MCPBA in dichloromethane yields only cis-stilbene oxide. In another
words, the epoxidation of 90 with MCPBA is not stereospecific in the basic biphasic
conditions, but is stereospecific when carried out in dichloromethane. The possibility of
91 isomerizing to 92 oxide was ruled out by a control experiment in which pure
cis-stilbene oxide was found to be stable to the biphasic expoxidation conditions.
Scheme 25.
O
O
MCPBA,
Ph
Ph
90
CH2Cl2/H2O
Ph
Ph
91
Ph
Ph
92
The biphasic epoxidations of cis-stilbene by MCPBA in dichloromethane rapidly
stirred with aqueous solutions of different compositions were also investigated. In a
rapidly stirred mixture of dichoromethane and plain water, epoxidation with MCPBA of
90 yields only cis epoxide 91. If the water solution contains sodium bicarbonate, sodium
- 115 -
carbonate or sodium phosphate, trans epoxide 92 is the major product formed in relative
yields of approximately 90%. When hydroxide is used as a base, the results depended on
the NaOH : MCPBA ratio. When excess sodium hydroxide is used, no epoxidation of
cis-stilbene occurs. When the NaOH : MCPBA mole ratio is ~0.5, however, trans epoxide
92 is the major product.
It was also observed that, when 2.5 eq of MCPBA in dichloromethane is slowly
added at constant rate via a syringe pump to a rapidly stirred solution of 1.0 eq
cis-stilbene in dichloromethane with excess sodium carbonate in water solution,
epoxidation does not occur until approximately 10-20% of the MCPBA solution is added.
Initially, cis-stilbene oxide is formed as the major product and tran-stilbene oxide is
formed as a minor product. Upon addition of additional MCPBA, the ratio of trans
epoxide 92 cis epoxide 91 increases until trans-stilbene oxide becomes the major
product.
2. Special Biphasic Epoxidation Procedure
The biphasic epoxidation procedure that yielded the greatest amount of trans
epoxides from the reaction of cis olefins with peroxyacids is summarized as follows. Pure
MCPBA ( 1.0 eq. ) was added to a vigorously stirred mixture of dicholoromethane and a
water solution of sodium carbonate, sodium bicarbonate, sodium phosphate, or sodium
hydroxide. The mixture was rapidly stirred with a stir bar. An aliquot of cis olefin
- 116 -
0.05-0.1 eq was injected through a syringe. After being stirred for 10 min, the
dicholoromethane phase was separated and washed with excess sodium carbonate
solution to remove the remaining MCPBA. An 1H NMR spectrum was recorded on the
residue. The chemical shifts of the cis and trans epoxide hydrogens were compared with
the chemical shifts of authentic cis and trans epoxides purchased from Adrich. The ratios
of cis and trans epoxides were measured by comparing the integrals of the epoxide
hydrogen absorption. The resulting epoxides were shown to be stable under the reaction
conditions: both cis and trans epoxides did not isomerize or decompose when subjected
individually to reaction conditions for 30 min.
3. Factors in Determining Yields of trans Epoxides from cis Olefins
In order to test if steric repulsion between the substituent groups is the main factor
that
determines
the
cis/trans
product
ratio,
cis-β-methylstyrene
(93)
and
cis-β-deuteriostyrene (96) were also epoxidized with MCPBA in biphasic conditions. The
biphasic epoxidation of cis-β-methylstyrene gives mostly trans epoxide 94 (> 85%) – a
result similar to that for biphasic epoxidation of cis-stilbene. Epoxidation of
cis-β-deuteriostyrene (98) gives trans and cis epoxide 97 and 98 in a 40:60 ratio. Because
deuterium and hydrogen have similar sizes, the maximum tran deuteriuo epoxide 97: cis
deuterio epoxide 98 ratio is expected to be about 50:50. cis-β-Methylstyrene oxide and
cis-β-deuteriostyrene oxide are stable to reaction conditions. Therefore, steric repulsion
- 117 -
between the cis-substituent groups is not the only factor causing non-stereospecific
epoxidation.
Scheme 26.
O
O
MCPBA,
Ph
CH3
CH2Cl2/H2O
Ph
CH3
Ph
CH3
> 85%
Na2CO3
93
94
95
O
O
MCPBA,
Ph
D
CH2Cl2/H2O
Na2CO3
Ph
D
40%
96
97
Ph
D
60%
98
Biphasic epoxidation of olefins with functional groups other then phenyl group
were also carried out. Experimental results showed that the biphasic epoxidations of
cis-2-hexen-1-ol, cis-3-hexene-1-ol and cis-2-hexene also yield trans epoxides as minor
products. (Scheme 27) The cis epoxides are all stable under the reaction conditions.
- 118 -
Scheme 27.
O
O
MCPBA,
H3CH2CH2C
CH2OH
CH2Cl2/H2O
H2CH2CH3C
CHOH
H2CH2CH3C
CH2OH
65%
35%
O
O
MCPBA,
H3CH2C
CH2CH2OH
CH2Cl2/H2O
H2CH3C
CHOH
H2CH3C
40
H3CH2CH2C
CH3
CH2Cl2/H2O
60%
O
O
MCPBA,
CH2CH3
H2CH3C
CH3
28%
H2CH2CH3C
CH3
72%
The biphasic epoxidations of cis-stilbene with other organic solvents were also
investigated. The biphasic epoxidation of cis-stilbene gave mostly trans-stilbene oxide
when the organic solvent was either diethyl ether or benzene and sodium carbonate was
in the aqueous phase.
In order to investigate if water plays a role in this unusual non-stereospecific
epoxidation, 0.05-0.1 eq of cis-stilbene was epoxidized with 1 eq of pure MCPBA with
0.5 eq of NaOH in polar solvents such as methanol and ethanol, where the reaction
solution is a single phase. Epoxidation with these conditions is stereospecific. Thus,
water and biphasic conditions are essential for the formation of trans epoxide as the major
product. Epoxidation of cis-stilbene was also tried out with just 1.0 M sodium carbonate
solution and pure MCPBA without dichloromethane. Under these reaction conditions the
epoxidation is much slower. However, trans product 92 (less than 20% olefin was
- 119 -
converted) was still found. The presence of an organic phase is therefore not essential for
the formation of trans epoxide 92, but it does speed up epoxidation and yields of trans
epoxide are greater. This result is consistent with two competing epoxidation reactions: a
stereospcific epoxidation reaction occurring in the organic phase and a non-stereospecific
epoxidation reaction that occurs at the water-dicholormethane interface or in a micell-like
environment.
In a more slowly stirred biphasic mixture, the relative yield of trans-stilbene was
found to be < 50%. Results of basic biphasic epoxidation of olefins and ratios of the cis
and trans epoxides are summarized in Table 11. Results for epoxidations of cis-stilbene
with different basic solutions are summarized in Table 12. Results for epoxidation of
cis-stilbene in different solvent systems are summarized in Table 13.
- 120 -
Table 17. Product studies on biphasic epoxidation of oleins with different funtional
groups
Alkene
( 0.05-0.1 eq )
CH3
D
HOH2C
HOH2CH2C
H3C
(CH2)2CH3
CH2CH3
(CH2)2CH3
Conditions
( 10 mL CH2Cl2/ 10
mL Aqueous
Solution)
Cis Product
(%)
Trans Proudct
(%)
1M Na2CO3
1 eq. MCPBA
5
95
1M Na2CO3
1 eq. MCPBA
<2
>98
1M Na2CO3
1 eq. MCPBA
5
95
1M Na2CO3
1 eq. MCPBA
62
38
1M Na2CO3
1 eq. MCPBA
65
35
1M Na2CO3
1 eq. MCPBA
60
40
1M Na2CO3
1 eq. MCPBA
72
28
.
- 121 -
Table 18. Studies of the effect of different bases on biphasic epoxidation of
cis-stilbene (0.05-0.1 eq alkene, 1 eq MCPBA)
CH2Cl2 (10 mL) and
Base (10 mL)
NaHCO3 (1.0 M)
Na2CO3 (1.0M)
Na3PO4 (1.0 M)
NaOH (0.25 eq)
NaOH (0.50 eq)
NaOH (0.75 eq)
NaOH (1.0 eq)
Water
Cis Product (%)
Trans Product (%)
6
5
8
87
72
23
0a
100 b
94
95
92
13
28
77
0
0
a
Epoxidation did not occur. bNo base is present in the water and less than
50% olefin was converted.
Table 19. Effects of organic solvent change on epoxidation of cis-stilbene
(0.05-0.1 eq alkene, 1 eq MCPBA )
Condition (water phase: 10 mL
1.0 M Na2CO3)
No CH2Cl2
Cis Product (%)
Trans Product (%)
90
10
10 mL CH2Cl2
5
95
10 mL Benzene
4
96
10 mL Diethyl Ether
79
21
10 mL MeOH (0.5eq, NaOH) a
100
0
10 mL EtOH (0.5eq, NaOH) a
100
0
a
The reaction mixture was clear and these reactions were carried out
without a water phase.
- 122 -
C. Discussion
1. Possible Mechanisms
Our studies of the biphasic epoxidation of cis olefins to form trans epoxides
clearly indicate that the mechanism is not a concerted one. The observation that the
cis/trans epoxide product ratio changes throughout the course of reaction when 2.5 eq. of
MCPBA
is
slowly
added
to
1.0
eq.
of
cis-stilbene
in
rapidly
stirred
dichloromethane/Na2CO3 ( 10 eq. )-water mixture indicates that there are two competing
mechanisms, a concerted reaction leading to cis-stilbene oxide and a stepwise reaction
leading to trans-stilbene oxide. The “butterfly” mechanism proposed for the concerted
reaction mechanism involves intramolecular proton transfer from the terminal peroxy
oxygen of the peroxyacid to the carbonyl oxygen in a five-membered ring transition state.
In the biphasic condition, there are peroxyacid anions that can serve as bases that can
interrupt the intramolecular proton transfer and thus change the mechanism from
concerted to stepwise.
It has been observed that in peroxyacid epoxidation, certain electron-deficient Zand E-alkenes give trans epoxide products. A two-step mechanism involving nucleophilic
attack of peroxyacid anion at the β carbon to form a α carbanion, followed by ring closure
(Scheme 28),87 has been proposed.
- 123 -
Scheme 28.
Ph
ArCO2
NO2
MCPBA
Ph
NO2
pH 9-10
ArCO2
O
NO2
O
Ph
NO2
O
Ph
NO2
Ph
A similar mechanism might account for the formation of trans epoxides from the biphasic
epoxidation of cis-stilbene (Scheme 29). However, a phenyl group is not really as
effective as a nitro group in stabilizing a carbanion intermediate, and this mechanism
from the non-concerted epoxidation of cis-stilbene is highly unlikely.
Scheme 29.
Ph
ArCO2
Ph
MCPBA
Ph
Ph
pH 9-10
ArCO2
O
Ph
Ph
O
O
Ph
Ph
Ph
Ph
A third possible mechanism is summarized in Scheme 30. In this mechanism a
carbocation stabilized by the phenyl group is formed. If this carbocation is sufficiently
stable, the C-C bond might rotate to release the steric repulsion, and base-induced ring
closure might then occur to give trans epoxide. However, cis-2-hexene is also epoxidized
under biphasic conditions to give both cis and trans epoxides. It is known that a simple
tertiary carbocation reacts with water/trifuoroethanol (H2O/TFE) solvent with an
estimated rate constant of ~1012 s-1, which is somewhat faster than bulk solvent
- 124 -
reorganizes.88 A simple secondary carbocation is predicted to react with water even faster
than a tertiary carbocation. The rate of secondary carbocation reacting with water is
predicted to exceed to rate of bond vibration (~10-13s-1). Therefore, a secondary
carbocation will not have sufficient lifetime in water to exist as an intermediate. A
carbocation intermediate is therefore highly unlikely to account for the reaction of
cis-2-hexene to form trans-2-hexene oxide. There must be another mechanism that
accounts for the formation of trans epoxides from cis olefins.
Scheme 30.
OCAr
O
O
H
H
H
HO
MCPBA
CH2Cl2/Na2CO3
H
H
O
O
H
OH
A forth possible mechanism for non-stereospecific epoxidation is given in
Scheme 31. Reaction of MCPBA with cis-stilbene, for example, might occur by a
syn-addition mechanism to yield a β-hydroxy ester. Rotation about the α,β C-C bond
- 125 -
followed by hydroxide-deprotonated epoxide ring formation would yield the trans
epoxide.
Scheme 31.
O
O
O
O
Ar
HO
H
H
MCPBA
Ar
O
H
CH2Cl2/Na2CO3
100
99
O
O
Ar
H
H
O
O
O
O
H
OH
In order to test whether this mechanism explains the formation of trans-stilbene
oxide, meso-hydroxy ester 100 was synthesized by treating meso-stilbene glycol 99 with
meta-chlorobenzoyl chloride. In the synthesis of the hydroxyl ester 100, only part of the
diol was converted (30%) to ester. However, treatment of this reaction mixture with
aqueous sodium carbonate yielded only diol 99, and no epoxide was detected (Scheme
32).
- 126 -
Ar
Scheme 32.
OsO4, N-methylmorphorline oxide
HO
H
OH
H
CCl4/ Acetone/t-BuOH/water
O
H
O
101
ide
chlor
l
y
o
z
en
lorob
m-ch
in e
Pryd
Na2CO3
O
H
OH
100
Scheme 33.
O
O
Ar
MCPBA in CH2Cl2
Ph
Ph
Na2CO3, water
Ar
O
O
OH
O
Ph
H
H
Ph
O
H
H
Ph
O
H
Ph
102
OH
O
O
O
O
Ar
The covalent intermediate that we consider to be the most probable candidate in
the non-stereospecific epoxidation of cis olefins is a hydroxy peroxy ester 102 (Scheme
- 127 -
33). A possible mechanism for the formation of this intermediate in the biphasic
epoxidation of cis-stilbene and its conversion to trans-stilbene oxide is given in Scheme
33. The base-promoted epoxide-forming step is analogous to the mechanism proposed for
the epoxide-forming step in the epoxidation of olefins with strong electron-withdrawing
group (Scheme 29). MCPBA ( pKa ~ 8 ) is much less acidic than m-chlorobenzoic acid
( pKa ~ 3.8), and therefore m-chloroperoxybenzoate ion is a much better leaving group
than m-chlorobenzoate ion.
Scheme 34.
ArCO3
O
O
Ph
LiBr
Ph
Amberlyst
99% ACN
Ph
OH
Ar
O
H
H
OH
O
H
H
Ph
Br
Ph
103
Ph
102
We have attempted the synthesis of by hydroxy peroxyester 100 addition of
m-chloroperoxybenzoate to (1R,2R)-2-bromo-1,2-diphenyl-ethanol 103. To date,
however, we have not succeeded in preparing the hydroxy peroxyester 102 proposed in
the mechanism for non-stereospecific epoxidation. However we think that the general
mechanism proposed in Scheme 34 is the most reasonable.
2. Nature of the Epoxidizing Reagent
Our results show that when MCPBA is fully de-protonated by reaction with
hydroxide ion before addition of cis-stilbene, epoxidation does not occur. The
peroxycarboxylate ion is therefore not the epoxidizing reagent. When base is not present
in the water phase of the biphasic epoxidation mixture, the epoxidation of cis-stilbene
- 128 -
with MCPBA is stereospecific. Therefore MCPBA is not the epoxidizing reagent of the
non-stereospecific epoxidation of cis olefins. Non-stereospecific epoxidation of olefins.
occurs only when both the peroxyacid and its conjugate base are present. It therefore
appears that the epoxidizing reagent for non-stereospecific epoxidation is a complex of
MCPBA and its conjugate base. The structure of this complex is uncertain. It could be a
simple hydrogen-bonded complex such as structure of 104, or a more complicated
polymeric complex.
O
O
O
Cl
O
H
O
O
101
Cl
The reaction condition that gives the highest yield of trans epoxide from cis
olefins involves pre-mixing 10 mL of dichloromethane, 10 mL of 1M Na2CO3 (10 mmol)
and ~ 350 mg (~ 2 mmol ) of MCPBA. Then a small amount of cis-stilbene (10-20 mg,
0.05-0.10 mmol) is added to the rapidly stirred reaction mixture. In order to determine if
the epoxidizing reagent were soluble in the dichloromethane phase, a control experiment
was run in which all reagents except the olefin were pre-mixed, and the dichloromethane
layer was separated from the water layer. The dichloromethane phase did contain a
significant amount (50 mg) of m-chlorobenzoyl peroxide, but when olefin was added to
the dichloromethane phase, no epoxidation occurred. The epoxidation reagent must
therefore be in the water phase or present as an insoluble complex. The epoxidation
- 129 -
reaction may be occurring on the surface of a complex or in a micelle-like environment.
Additional attempts to synthesize hydroxyperoxy ester 102 will be the base of a future
investigation by another student.
C. Experimental
1. Purification of MCPBA Commercial MCPBA (10.5g) in CHCl3 (75 mL) was
extracted twice with Na2HPO4 solution (5.0 g in 25 mL water). The organic layer was
washed with saturated NaCl solution once. The organic layer was separated and dried
over Na2SO4. Evaporation of solvent yielded 5.5 g of pure MCPBA. 1H NMR (CDCl3,
400 MHz): δ 11.56 (b, 1H), 8.00-7.97 (m, 1H), 7.90-7.87 (m, 1H), 7.64-7.61 (m, 1H)
7.45 (apparent t, 1H)
2. Synthesis
a. Synthesis of cis-β-Deuteriostyrene
(2S,3R)-Dibromo-3-phenyl-propionic acid. The procedure in ref.
89
were followed in
this bromination reaction. trans-Cinnamic Acid (5.0 g, 33.7 mmol) in 200 mL CHCl3 was
stirred in an ice bath. Bromine (5.39 g, 33.7 mmol) in 50 mL CHCl3 was dropwise added.
The solution was allowed stir for another 2 h at rt after the addition of bromine. The
solvent was removed under reduced pressure to give 10.2 g slightly yellow solid.
Recrystallization of this material from ethyl acetate/ether afforded 6.78 g white solid
(yield 65.3%). m.p. 110-111 °C.
1
H NMR (CDCl3, 400 MHz): δ 7.50-7.38 (5H), 5.32 (d,
- 130 -
J = 11.9 Hz, 1H), 4.87 (d, J = 11.9 Hz, 1H). The product has very little of the 2S,3S
isomer (< 3%).
(E)-β-Bromostyrene. The procedure in ref.
89
was followed in this debromination. A
mixture of (2S,3R)-Dibromo-3-phenyl-propionic acid (5.5 g, 17.9 mmol) and Na2CO3
(18.93 g, 179 mmol) in 150 mL acetone was stirred under N2 overnight. Most all the
acetone was then removed under reduced pressure. Water was added and the mixture was
extracted twice with 80 mL diethyl ether. The organic layer was separated and dried over
Na2SO4. Evaporation of the solvent gave 3.1 g (94%) of a yellow liquid. Distillation at
50 °C under 0.02 mm Hg gave 2.84 g yellow liquid. 1H NMR (CDCl3, 400 MHz): δ 7.67
(d, J = 6.9 Hz, 2H), 7.38-7.29 (3H), 7.06 (d, J = 8.2 Hz, 1H), 6.42 (d, J = 8.2 Hz, 1H).
The product had very little of E isomer (< 3%).
(E)-β-Deuteriostyrene. The procedure in ref.
90
was followed in this reaction.
(E)-β-bromostyrene (2.3 g, 12.6 mmol) in 14 mL of dry diethyl ether (distilled from fresh
sodium) was cooled down to -78 °C. t-Butyl lithium in pentane (1.7 M, 12 mL) was
added slowly through a syridge. The mixture was stirred for another 30 min and D2O (1.5
mL, > 99%) was dropwise added. The reaction mixture was slowly warmed up to rt.
Brine (20 mL) was added to dissolve the lithium salt. The mixture was then extracted
twice with ether (30 mL). The organic layer was separated and dried over Na2SO4.
Evaporation of ether gave 1.10 g (yield 83.1%) of yellowish liquid. 1H NMR (CDCl3, 400
MHz): δ 7.41-7.23 (5H), 6.75-6.69 (m, 1H), 6.23 (d, J = 10.6 Hz, 1H). The reaction
contained very little of the E isomer (< 5%).
- 131 -
b. Synthesis of (1R, 2R)-2-Bromo-1,2-diphenyl-ethanol(103).
91
cis-Stilbene oxide
(100 mg, 0.51 mmol), lithium bromide (177.0 mg, 2.04 mmol), and acidic Amberlyst
(224 mg, 0.51 mmol) were stirred in 6 mL 99:1 acetonitrile/water for 1 hour. The catalyst
was removed by filtration and the acetonitrile was removed under reduced pressure. The
bromohydrin was dissovlved in 30 mL diethyl ether, and the ether layer was washed with
10 mL brine. The organic layer was separated and dried over Na2SO4. Evaporation of
ether give 132 mg (yield 94%) solid product. This product was used without further
purification. 1H NMR (CDCl3, 400 MHz): δ 7.25-7.17 (10H), 5.11 (d, J = 8.2 Hz , 1H),
5.04 (d, J = 8.2 Hz, 1H), 3.02 (b, 1H).
c. Ring-closure of 2-Bromo-1,2-diphenyl-ethanol (103) to Give cis-Stilbene Oxide.
Bromohydrin 103 (25 mg) was dissolved in 5 mL of THF. Sodium carbonate solution (2
mL, pH 10) was added and the solution was kept stirred for 30 min. After most of the
THF was removed, the mixture was extracted with diethyl ether. The organic layer was
separated and dried over Na2SO4. Evaporation of the ether give a solid residue. The 1H
NMR of this material showed that it was a mixture of bromhydrin 103 and cis-stilbene
oxide (~ 70%). This result shows that the bromohydrin 103 prepared from cis-stilbene
oxide can be converted back to cis-stilbene oxide with basic sodium carbonate solution.
- 132 -
H
COOH
Br
Br
Ph
H
H NMR (CDCl3, 400 MHz): δ 7.58 (d, J = 8.2 Hz, 1H), 6.95-6.92 (2H), 6.75 (dd, J1 = 1.4 Hz, J1= 9.6 Hz,
1H), 6.45 (dd, J1 = 4.1 Hz, J = 9.6 Hz, 1H), 4.43 (d, J = 4.1 Hz, 1H), 4.04 (m, 1H), 3.83 (s, 3H).
1
- 133 -
Ph
1
Br
H NMR (CDCl3, 400 MHz): δ 7.50-7.38 (5H), 5.32 (d, J = 11.9 Hz, 1H), 4.87 (d, J = 11.9 Hz, 1H).
- 134 -
Ph
1
H NMR (CDCl3, 400 MHz): δ 7.41-7.23 (5H), 6.75-6.69 (m, 1H), 6.23 (d, J = 10.6 Hz, 1H).
- 135 -
D
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