TOWARD THE SYNTHESIS OF AZIDO-CROWN ETHERS
WITH UNUSUAL NITRENE REACTIVITY
A THESIS
SUBMITTED TO THE GRADUATE SCHOOL
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF
MASTER OF SCIENCE
BY
MEGAN E. WILLIAMS
ADVISOR: DR. JAMES S. POOLE
BALL STATE UNIVERSITY
MUNCIE, INDIANA
JULY 2011
TOWARD THE SYNTHESIS OF AZIDO-CROWN ETHERS WITH
UNUSUAL NITRENE REACTIVITY
A THESIS
SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF
MASTER OF SCIENCE
BY
MEGAN E. WILLIAMS
Committee Approval:
Committee Chairperson
Date
Committee Member
Date
Committee Member
Date
Department Approval:
Department Chairperson
Date
Graduate Office Check:
Dean of Graduate School
Date
Ball State University
Muncie, IN
July 2011
Acknowledgements
First and foremost I would like to thank the Ball State University Chemistry
Department for accepting my application and allowing me to pursue a Master’s degree.
The faculty members in this department have been very helpful and encouraging
throughout this journey, and I appreciate all their efforts.
I’d especially like to thank Dr. James Poole for accepting me into his research
group. His guidance and support helped get me to where I am at today and I will always
be appreciative of everything I have gained from this experience. I feel confident in
saying that he has helped shape me into a better chemist as I leave this program. I’d also
like to thank my thesis committee members, Dr. Philip Albiniak and Dr. Tykhon Zubkov
for their time and effort spent helping shape my thesis into the best that it can be.
Without support from my family and my boyfriend, Matthew Haddock, I never
would have made it through this program. I am so grateful to my parents for their loving
support, and sometimes financial, throughout my academic career, helping shape me into
the woman that I am today. Matthew has been so supportive of my pursuits at higher
education and it means so much to me that he would put some of his goals on hold while
I pursued some of mine.
The opportunity that I’ve been given to further my education has been an amazing
learning experience for life and my future pursuits in higher education and career. Thank
you to everyone involved in the process of completing this degree.
i ABSTRACT
THESIS: Toward the Synthesis of Azido-Crown Ethers with Unusual Nitrene Reactivity
STUDENT: Megan E. Williams
DEGREE: Master of Science
COLLEGE: Sciences and Humanities
DATE: July 2011
PAGES: 65
It has been shown that photolysis of 4-azidopyridine N-oxide yields the singlet
nitrene, which undergoes intersystem crossing at room temperature to generate triplet 4nitrenopyridine N-oxide. The room temperature photochemistry is dominated by triplet
nitrene chemistry leading to the formation of the azo-dimer. This unusual behavior is a
result of selective stabilization of the lowest singlet state of the nitrene by the N-oxide
group.
In this study, we wish to investigate the effect of complexation of the N-oxide
group with a metal cation on the kinetics and reactivity of 4-nitrenopyridine N-oxide and
related compounds. It is envisaged that complexation will alter the polarity of the N-oxide
bond making it less capable of spin delocalization in the nitrene.
Complexation may be achieved through two different methods: complexation
with cations in aqueous salt solutions and complexation of cations inside crown ethers.
Crown ethers provide useful models due to the selectivity of complexation with different
ions based on ring size and slower diffusion of cations away from the N-oxide group.
Progress toward the multi-step synthesis of crown ethers containing the 4azidopyridine N-oxide substructure is described herein.
ii Table of Contents
Page #
List of Schemes
List of Figures
List of Tables
Chapter 1
Chapter 2
Chapter 3
iv
v
v
Introduction
1.1 An Overview of the Chemistry of Azides
1.2 Arylnitrenes
1.2.1 Substituted Phenylnitrenes
1.2.2 Nitrenopyridine N-oxides
1.3 Crown Ethers and Synthetic Targets
1
5
8
11
16
Experimental Methods
2.1 Materials
2.2 Instrumentation
2.3 Experimental Methods
19
19
20
Results and Discussion
3.1 Synthetic Strategies
3.2 Synthesis of 4-bromo-2,6-pyridinedimethanol
3.3 Synthesis of Compound 5
3.4 Synthesis of Compound 6
3.5 Synthesis of Compound 7
3.6 Attempts to Incorporate the Azido- group
27
28
31
32
35
38
Bibliography
Appendix A
41
Experimental Spectra
44
iii List of Schemes
Page #
Chapter 1
Introduction
Scheme 1.1
Scheme 1.2
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Azide formation via diazonium salts
Azide formation via nucleophilic substitution
Azide reduction to form a primary amine
1,3-dipolar cycloaddition reactions of organic azides
Photolysis/thermolysis of phenyl azide to form phenylnitrene
Four candidate structures of reactive intermediate formed in
photolysis of phenyl azide
Mechanism of phenyl azide thermo- and photochemistry
Effect of o-substitution on cyclization reactions of phenylnitrene
Potential mechanism of the photolysis of 4-azidopyridine N-oxide
Iminyl-aminoxyl biradical stabilization of 4-nitrenopyridine Noxide
Low temperature Photoproducts of 3-azidopyridine N-oxide
Proposed Retrosynthetic Scheme for 4-azido-2,6-pyrido-18crown-6 N-oxide
Scheme 6
Scheme 7
Scheme 8
Scheme 9
Scheme 10
Scheme 11
Chapter 3
Results and Discussion
Scheme 12
Scheme 13
Scheme 14
Scheme 15
Scheme 16
Scheme 17
Scheme 18
Scheme 19
Scheme 20
Scheme 21
Retrosynthesis of 2,6-pyrido-18-crown-6 derivative 6
Synthesis of Compound 1
Synthesis of Compound 2
Synthesis of Compound 3
Synthesis of Compound 4
Synthesis of Compound 5
Attempted Syntheses of Compound 6
Attempted Syntheses of Compound 7
Attempted Synthesis of Compound 8
Synthesis of 19-azido-3,6,9,12,15-pentaoxa-21azabicyclo[15.3.1]-henicosa-1(21),17,19-triene (9)
iv 1
1
2
2
4
7
8
10
12
13
14
18
27
28
29
30
30
31
32
35
38
39
List of Figures
Page #
Chapter 1
Introduction
Figure 1
Figure 2
Figure 3
Figure 4
Strucutre of AZT
Four candidate structures of reactive intermediate formed in
photolysis of phenyl azide
Effect of o-substitution on cyclization reactions of phenylnitrene
Azido-functionalized cryptand
Chapter 3
Results and Discussion
Figure 5
NMR Comparison of 6 & 7
3
6
15
17
35
List of Tables
Page #
Chapter 1
Introduction
Table 1
Summary of Calculated EST for Nitrenes (kcal/mol)
v 12
Chapter 1 – Introduction
1.1 An Overview of the Chemistry of Azides
Organic azides (with azido functional group –N3) have received a great deal of
attention in the literature as important synthetic intermediates due to their relative ease of
formation and their useful reactivity. Two of the most common forms of azide formation
are via diazonium salts or nucleophilic subsitution.1
Aryl diazonium salts react with
azide ions without the use of catalysts to form the corresponding aryl azide (Scheme 1).
Generally, alkali metal azides or trimethylsilyl azides act as the azide source.
N
1.
N
NaN3
N3 + NaX + N2
X
2.
R
X
+
NaN3
R
N3
Scheme 1: (1) Azide formation via diazonium salts. (2) Azide formation via
nucleophilic substitution
2 Nucleophilic substitution (via SN1 or SN2) to form alkyl azides is often favorable due to
the high nucleophilicity of the azide ion (Scheme 1), and its low to moderate basicity
(pKa HN3 = 7-9).2 The most common azide source is sodium azide, although others can
be used. Leaving groups include, but are not limited to, halides, carboxylates, and
sulfonates.3
Azides are synthetically useful in reactions involving 1,3-dipolar cycloadditions and
formation of primary amines. Primary amines can be generated from the reduction of an
azide (Scheme 2).3 A wide range of different reducing agents can be used, including
LiAlH4, NaBH4, and H2/catalyst.
R
N
N
[H]
N
R
NH2
Scheme 2: Azide reduction to form a primary amine
1,3-Dipolar cycloadditions are commonly used in synthetic organic chemistry as a
method to generate heterocyclic ring systems from a variety of substrates (1,3-dipoles),
including azides (Scheme 3).4
R
R
N3
+
H
N
N
R
N3 + H
N
N
N
X
H
R
R
N
X
X
N
N
H
N
X
X
R
H
N
N
X
Scheme 3: 1,3-dipolar cycloaddition reactions of organic azides
N
H
3 Alkenes or alkynes can be used as the dipolarophile, but all that is essential is a π bond.
The reaction proceeds via stereospecific syn-addition to yield 1,2,3-triazolines from
alkenes, and triazoles from alkynes. Reaction is often facilitated by the addition of a
copper salt as catalyst: so-called “click” chemistry.5,6 When both the 1,3-dipole and the
dipolarophile are unsymmetrical, two possible products can be generated: 1,4- and 1,5regioisomers. It may be shown that both steric and electronic factors play a role in
determining regioselectivity, but frontier orbital interactions are often dominant factors.
Typically, the most energetically favorable orientation in the transition state is that which
involves complementary interaction between the frontier orbitals of the 1,3-dipole and the
dipolarophile.4 The most common additions are those dominated by interactions between
the LUMO of the dipolarophile and the HOMO of the 1,3-dipole, but reactions
dominated by opposite interactions (“inverse-demand”) are also possible.
Azides are not limited to the role of synthetic intermediate, but may be a useful
functional group in its own right. The azido- group has been investigated as a potential
pharmacophore: one specific organic azide, 3’-Azido-2’,3’-dideoxythymidine (AZT,
Figure 1), has received a great deal of attention due to its antiretroviral activity.7
O
NH
HO
N
O
O
N3
Figure 1: Structure of AZT
4 AZT was the first approved treatment for HIV/AIDS therapy introduced in the early
1990’s. It slows the spread of HIV by inhibiting the reverse transcription process in
replication. The azido group increases the lipophilic nature of AZT, allowing it to diffuse
across cell membranes and cross the blood-brain barrier. AZT does not completely stop
the spread of the virus, so it is combined with other anti-viral drugs to help prevent the
chance of resistance. Another application of azides is in the form of sources of high
energy nitrogen. For example, glycidyl azide polymer (GAP) is studied as a potential
source of high-energy nitrogen in solid propellant.8 GAP acts as a propellant fuel-binder
in the mixture of fuel and oxidizer, that when mixed, create a high-energy explosive.
Aryl azides have also received a lot of attention due to their relatively high stability
and ability to act as thermo- and photochemical precursors of nitrenes (Scheme 4).9
Nitrenes are short-lived, highly reactive species that contain a nitrogen atom with only six
electrons in its valence shell.
N3
hv
!
N
Scheme 4: Photolysis/thermolysis of phenyl azide to form phenylnitrene
Applications of the nitrene chemistry of aryl azides include organic synthesis of azepine
derivatives,10 in the formation of electrically conducting polymers, and in photoaffinity
labeling.9 Photoaffinity labeling is a method of covalently binding chemical tags to the
active sites of protein molecules.11 A labeling reagent is converted by photolysis to a
reactive intermediate and specifically binds to the active site at the instant of photolysis.
5 The role and structure of aryl nitrenes in these reactions has been studied for many years,
but a clearer understanding of these systems emerged in more recent years with the
application of laser flash photolysis (LFP),12 low temperature matrix isolated IR,13 low
temperature glassy matrix EPR,14 and high-level ab initio molecular orbital (MO)
calculations.
1.2
Aryl Nitrenes
Arylnitrenes are highly reactive, short-lived intermediates generated by the
decomposition of aryl azides. They have six valence electrons that can exist in four
different possible electronic states (Figure 2, overleaf): triplet, open-shell singlet, and two
closed-shell singlet states.
The lone pair of electrons that exists in all states occupy a hybrid orbital rich in 2s
character. The triplet and open-shell singlet state have two nonbonding electrons that
both occupy pure 2p orbitals, differentiated by their spins. The triplet state has two
unpaired electrons with parallel spins, whereas the open-shell singlet state has two
unpaired electrons with opposite spins. Of the 2p orbitals, one is a 2pπ orbital that may
overlap with the π -system in the aromatic ring, and the other is a p orbital that lies in the
plane of the ring. The two different closed-shell singlet states have paired electrons and
are generally viewed as a linear combination of two canonical forms; either the paired
electrons lie in the in-plane p orbital or the 2pπ orbital.9
6 Figure 2: Energy level diagram for the electronic states of a nitrene
The triplet state is considered the ground state and is lowest in energy followed by
the open-shell singlet state, with the closed-shell singlet state highest in energy.
Calculations indicate that the singlet-triplet energy gap (EST) for phenylnitrene (the
archetype system) is approximately 14.8 kcal/mol.15
Early studies of the photolysis of phenyl azide in solution produced a polymeric
tar.7 In the presence of primary and secondary amines formation of azepine (5) was
observed. A reactive intermediate (C6H5N) was postulated to be trapped in the presence
of diethylamine, but the structure was unclear for many years. From the product
distributions obtained, four candidate structures were proposed (Scheme 5): singlet
7 nitrene (1), triplet nitrene (2), benzazirine (3), aza-1,2,4,6-heptatetraene (cyclic
ketenimine, 4).
1N
N3
3N
N
N
NHEt2
h!
1
2
3
4
N
5
NEt2
Scheme 5: Four candidate structures of reactive intermediate formed in
photolysis of phenyl azide
With the development of research techniques, a clearer mechanistic picture (Scheme 6)
has been developed describing the photochemistry and thermochemistry of phenyl azide.9
Upon photolysis (or thermolysis), singlet nitrene (1) is formed. At temperatures above
165K, cyclization to benzazirine 3 is favored, followed by rapid ring-opening to cyclic
ketenimine 4, typically the major trappable reactive intermediate in solution at room
temperature. In the absence of good nucleophiles, 4 undergoes polymerization.
At
temperatures below 165K, intersystem crossing (ISC) to triplet nitrene 2 (which is a
temperature independent process) becomes dominant relative to cyclization (a
temperature dependent process with a non-zero activation barrier). ISC is a slow process
because spin-flip from opposite electron spins to matching spins is formally spinforbidden. ISC is followed by dimerization of the nitrene or reaction of triplet nitrene
with starting azide to form azobenzene.
8 N
1N
N3
kexp
kcyc (kR)
hv
N
>165K
3
1
4
HNEt2
<165K
kisc
3N
NH
2
NEt2
dimerizes
N
N
N
5
NEt2
Scheme 6: Mechanism of phenyl azide thermo- and photochemistry
1.2.1 Substituted Phenylnitrenes
After gaining a better understanding of the mechanism for phenyl azide
photochemistry, substitution effects were studied using nitrene and ketenimine transient
absorption spectra in the near-UV/ visible region.9 Values for kOBS (the observed rate
coefficient for the decay of singlet nitrene and/or the growth of products) were measured
by the decay or growth of absorbance at the λmax of the transient species as a function of
temperature.
Construction of an Arrhenius plot for kOBS with 1/T shows a region of
9 linearity where cyclization and ring expansion (singlet nitrene chemistry) dominates;
which becomes non-linear and effectively temperature independent at lower
temperatures, where triplet chemistry dominates (Scheme 6). This value is associated
with temperature- independent rate of intersystem crossing, with rate coefficient kISC.
The location and type of substituent has shown to affect rates of cyclization or
ISC in different ways:
p-Substitution of phenylnitrene can enhance kISC depending on the nature of the
substituent.9 Heavy atom effect, observed with bromo or iodo groups, increases kISC by a
factor of greater than 20 relative to phenylnitrene.9
Heavy atom effect is the
enhancement of the rate of a spin-forbidden process, due to significant spin-orbit
coupling in an atom of high atomic number and therefore large orbital angular
momentum.15 Strong π -donors, such as methoxy or dimethylamino groups, also increase
kISC by 2-3 orders of magnitude. The mechanism by which these enhancements occur is
not clearly understood. Substituents such as methyl, trifluoromethyl, acetyl, fluoro, and
chloro, are not sufficiently strong π-donors or acceptors to significantly influence kISC.
Under some circumstances o- and m-substitution can enhance kISC as well, and the
degree of enhancement again depends on the substituent.9 For example, mono and di-ofluoro substitution on phenyl nitrene have shown to have no influence on ISC, whereas
di-o-cyano substitution slightly accelerates kISC. An o-methyl accelerates ISC by a factor
of approximately 3, and di-o-methyl has an even greater effect.9
In the case of p-substitution and rate of cyclization/rearrangement (characterized
by rate coefficient kR), large substitutent effects are not anticipated due to the distance of
substituents from the nitrene.9 Substituents such as methyl, trifluoromethyl, halogens,
10 and acetyl have little influence on kR. The effects of strong π-donating groups were
impossible to study due to faster kISC than kR at all temperatures. p-phenyl and cyano
groups depress kR and retard the rate of cyclization significantly, due to their radical
stabilizing properties. The substituents withdraw spin density from the ring, making
cyclization, which may be envisaged as an internal biradical coupling, less favored.
Photolysis of different o-alkyl substituted phenyl azides (methyl, ethyl, isopropyl)
showed cyclization of the singlet nitrene toward the unsubstituted o-carbon, indicating
that steric effects have an influence on the barrier to ring expansion (Scheme 7).
1N
N
N
Scheme 7: Effect of o-substitution on cyclization reactions of phenylnitrene
If the nitrogen atom moves away from the alkyl group to cyclize, steric strain is released
between the two groups. Alternatively, o-cyano and o-acetylphenyl groups undergo
cyclization both away from and toward the substituent. Cyclization away from the group
can be attributed to steric effects, whereas cyclization toward the group can be attributed
to spin localization electronic effects: localization of an unpaired electron at the carbon
where the substituent is attached, favored by the radical stabilizing nature of these
substitutents.9 Mono-substituted o-fluoro substitutents cause cyclization away from the
group due to a combination of steric effects and the electronegativity of the fluorine
atom. The electronegativity of fluorine also affects cyclization toward the group. If o,o-
11 difluoro substitution is present, ring expansion is inhibited and raises the barrier to
cyclization approximately 3 kcal/mol relative to the unsubstituted system.9
1.2.2 Nitrenopyridine N-Oxides
Azidoheteroaryl N-oxides, a subclass of aryl azides, have been studied due to their
potential as antitumor agents.16 N-oxide groups are expected to enhance water solubility
of these compounds, which may also be advantageous for potential photoaffinity agents.
The 3- and 4-nitrenopyridine-1-oxide systems have been studied by LFP, matrix isolation
IR and computational methods.17,18
If photolysis of 4-azidopyridine N-oxide proceeds in a similar manner as
phenylnitrene, the nitrene could either cyclize or go through ISC to form the triplet
(Scheme 8). Alternatively, reactions involving N-oxide photochemistry may be possible
(since these groups are photoactive in their own right), but were not found to be
significant in these systems.
12 1N
N3
N
N
hv
N
N
N
O
O
O
N
O
ISC
3N
O
N
N
N
N
O
N
O
Scheme 8: Potential mechanism of the photolysis of 4-azidopyridine N-oxide.
Experimental results showed that triplet nitrene chemistry is favored, even at room
temperature; and no cyclization products were observed.17 The much smaller singlettriplet energy gap of 4-nitrenopyrdine N-oxide relative to phenylnitrene (Table 1) results
in a modest enhanced rate of ISC.
Table 1: Summary of Calculated EST for Nitrenes (kcal/mol)a
Nitrene
0K
298K
phenylnitrene
15.7
15.8
4-nitrenopyridine
16.7
16.7
3-nitrenopyridine 1-oxide
16.4
16.4
4-nitrenopyridine 1-oxide
9.8
9.9
a Calculations
performed at B3LYP/6-31G* level of theory for 4-nitrenopyridine N-oxide, 4-pyridylnitrene,
and phenylnitrene to determine relative energies (kcal/mol) at the triplet and open-shell singlet states.
Singlet state energies were estimated by the sum method of Johnson et al. [Ref. 19]
13 Calculations indicate the cyclization/ring expansion pathway is thermodynamically
disfavored due to the effect of electron configuration. The open-shell singlet state is
preferentially stabilized due to resonance contributors with iminyl-aminoxyl biradical
character (Scheme 9), which increases the barrier to cyclization.
From this it is
reasonable to assume that a significant amount of spin density in the ring lies on the Noxide atoms. Diminution of spin density at sites o- to the nitreno group also makes
cyclization less favorable.
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
Scheme 9: Iminyl-aminoxyl biradical stabilization of 4-nitrenopyridine N-oxide
In the case of 3-nitrenopyridine N-oxide, different results are expected due to the
positioning of the azide in the 3-position on the pyridine ring. At this position, stabilizing
effects due to iminyl-aminoxyl biradical character are not present, so it is expected to
behave more like a typical phenylnitrene. Calculation of EST for this species confirm that
the splitting is similar in magnitude to that of phenylnitrene.18 At low temperature
photolysis of 3-azidopyrdine 1-oxide, the triplet nitrene is obtained.18 With prolonged
photolysis; the singlet state can be accessed, yielding cyclization and ring expansion
products. These results are interesting in that both possible modes of cyclization are
observed at low temperature, but that when cyclization occurs toward the N-oxide
14 moiety, the benzazirine analogue is more thermochemically favored than the ketenimine
analog (Scheme 10), which is unusual for a simple monocyclic aryl nitrene.
N
N
O
N
O
hv
N
N3
not obs.
ISC
N
O
N
N
1N
O
3N
O
N
N
N
O
N
not obs.
O
Scheme 10: Low temperature Photoproducts of 3-azidopyridine N-oxide
LFP experiments at room temperature yield polymeric tar in the absence of a nucleophilic
trap, but with the addition of diethylamine or dibutylamine, the intermediates can be
quenched. The trapped nitrene product is highly photolabile making characterization
difficult. Further study is needed to better understand products of the 3-azido species
generated at room temperature and their photochemistry.
In this study, we wish to investigate the effect of complexation of the N-oxide
group with a metal cation on the kinetics and reactivity of 4-nitrenopyridine N-oxide and
its analogs. It is envisaged that complexation will alter the polarity and polarizability of
the N-oxide bond making it less capable of spin delocalization of the nitrene. This in turn
15 should alter the selective stabilization of the singlet nitrene by the N-oxide moiety, which
in turn may alter the observed chemistry of this intermediate. It may also be possible that
the effect of such species may not be limited to purely electrostatic interactions:
complexation with large cations (which have large spin-orbit coupling interactions), may
also result in enhanced rates of ISC. In addition, the association of a charge should
decrease the likelihood of bimolecular chemistry (ie. dimerization of the triplet, or
polymerization of the singlet) due to Coulombic repulsion, and so new modes of
reactivity may be observed.
In principle, complexation may be achieved through two different methods:
complexation with cations in aqueous salt solutions and complexation of cations inside
crown ethers (Figure 3).
N3
N3
N
O
N
O
O
M+
O
M+
O
O
O
Figure 3: Modes of complexation of cations with N-oxide
Complexation in an aqueous salt solution is a less ideal method, because the metal
cations can easily diffuse away from the N-oxide, therefore yielding inefficient
complexation or too rapid exchange of cations. Crown ethers provide a more favorable
16 method for achieving complexation due to the ability of the crown to help slow diffusion
of cations away from the N-oxide group. Also, selectivity of complexation with different
cations can be achieved based on crown ether ring size.
1.3
Crown Ethers and Synthetic Targets
Charles Pedersen at the DuPont Company discovered crown ethers in the early
1960’s.20 Simple crown ethers are named as X-crown-Y, with “X” denoting the total
number of atoms in the crown and “Y” denoting the total number of oxygen atoms. An
important characteristic of crown ethers is that they can complex with alkaline earth and
alkali metals as well as ammonium ions, by providing a stabilizing solvation shell around
these guest species. This type of interaction is known to enhance the solubility of
inorganic salts in organic solvents, which allow many reactions to be performed under
non-aqueous, aprotic conditions.20 In addition, the salvation of the cationic component of
a salt effectively sequesters it from solution, leaving a “bare” counterion, that often
exhibits enhanced reactivity toward organic substrates in solution.20
Crown ethers have been studied in their use to aid complexation of alkali cations
with aryl nitrenes and their impact on nitrene chemistry.21,22 A series of cryptand-like
molecules functionalized with intraannular azido groups (Figure 4) were studied using
LFP.
17 N
N
N3
O
O
O
Figure 4: Azido-functionalized cryptand
Initially the singlet nitrene is formed and is reasonably long-lived (~1.4 µs) as a result of
substitution in both o-positions.20 Di-substitution in o-positions are known to slow the
rate of rearrangement, shown in the case of di-o-dimethylphenylazide which has a
lifetime of ~12 ± 1 ns.9 At room temperature, ISC competes with rearrangement, and
both singlet and triplet products are observed, which is an effect of isolating the nitrene
moiety from readily reactive groups and not allowing it to cyclize. Experimental results
showed that the binding of Na+ and K+ in these systems had minimal effect on these
experimental outcomes.20,21
In the above studies, the authors were interested in the effect of direct
complexation of the nitrene by cations on the nitrene chemistry. In our case, we are
investigating the effect of complexation at a remote group (i.e. the N-oxide) on the
observed chemistry of the nitrene. We want to incorporate an azidopyridine N-oxide
moiety within a crown ether to help facilitate complexation with a metal cation.
In the retrosynthesis of the azidopyridine N-oxide (Scheme 11), the azido group
replaces a good leaving group (bromide). To form the N-oxide group, the nitrogen in the
pyridine ring must be oxidized. It is postulated that these two steps could happen in
18 either order with similar results. The crown ether would be made from a glycol and a
pyridine ring with bromomethyl (or other good leaving groups) substituents ortho- to the
pyridine nitrogen.
O
N
N3
O
O
O
O
O
Br
N
O
O
O
O
O
O
O
O
Br
N
Br
+
Br
N
O
Br
O
HO
O
O
O
O
OH
Scheme 11: Proposed Retrosynthetic Scheme for 4-azido-2,6-pyrido-18-crown-6 N-oxide
The first target crown ether is generated from tetraethylene glycol to yield an 18-crown-6
ring, which is suitable for smaller metal cations, such as Na+. Different crown ethers can
be generated from larger glycols that would be more suitable for complexation with
larger cations.
This work describes progress toward the multi-step synthesis of 4-azido-2,6pyrido-18-crown-6 N-oxide, as an archetype of the indicated crown systems.
Chapter 2 – Experimental Methods
2.1 Materials
Tetraethylene glycol and diethyl oxalate were obtained from commercial sources,
distilled under reduced pressure and stored over 3Å molecular sieves. Acetone was
distilled under argon, collected over 3Å molecular sieves and used immediately after
distillation.
All other materials were purchased from commercial sources and used
without further purification.
2.2 Instrumentation
Proton (1H) and carbon-13 (13C) nuclear magnetic resonance (NMR) spectra were
obtained on a 300 or 400 MHz JEOL Eclipse NMR Spectrometer. Chemical shifts were
reported downfield from reference (residual protonated solvent resonance) values for
CDCl3 or d6-DMSO solvents as indicated. IR spectra were obtained on a Perkin Elmer
Spectrum 100 FT-IR Spectrometer using an ATR accessory with a diamond element.
20 2.3 Experimental Methods
4-Oxo-4H-pyran-2,6-dicarboxylic acid (Chelidonic Acid, 1)23
O
HO
OH
O
O
O
Sodium metal (30.8 g, 1.34 mol) in mineral oil, washed with hexanes and blotted dry,
was slowly added over an hour to 400 mL of absolute ethanol and the resultant heated
under reflux conditions under argon for an additional hour. Half of the solution was
cooled until a precipitate formed and the other half was kept warm. Dry acetone (48.9
mL, 38.7 g, 0.67 mol) and ethyl oxalate (93.0 mL, 100 g, 0.68 mol) were added to the
cooled sodium ethoxide solution with stirring. The resultant solution was heated until
solid precipitated from solution, and the second half of the sodium ethoxide solution was
added, along with 99.1 mL (106.7 g, 0.73 mol) of ethyl oxalate. The solution was heated
on an oil bath at 110oC until 100 mL of the solvent was removed, then cooled to room
temperature. The solid sodium derivative was removed using a glass rod and treated with
a mixture of 200 mL of 32% HCl and 600 g of cracked ice. The dienol intermediate was
isolated by filtration and washed with about 65 mL of ice water. A sample of the
resulting dienol intermediate solid was removed and analyzed by IR.
IR (ATR): 2983, 2932, 2899, 2872 (methylene C-H asym/sym stretches); 1730 (C=O
stretch, ester); 1630 (C=O stretch, ketone) cm-1
The crude material was heated with 200 mL of conc. HCl on an oil bath at 95 oC
for twenty hours. The solution was cooled to 20 oC, and the product isolated by filtration,
21 then washed with ice water (2 x 50 mL). The obtained solid was dried to constant weight
to yield chelidonic acid (52.8 g, 86%) as an off-white solid, mp. 263-264 oC (lit. 267
o
C).23
1
H NMR (d6-DMSO, 400 MHz.): δ= 6.96 (H; s, 2H) ppm
13
C NMR (d6-DMSO, 100 MHz.): δ= 179.8, 161.3, 154.5, 119.4 ppm
IR (ATR): 3111, 3076 (aryl C-H stretch); 2830 (O-H stretch, broad); 1716 (C=O ketone
stretch); 1640 (C=O acid stretch) cm-1
4-hydroxy-2,6-pyridinedicarboxylic acid (Chelidamic Acid, 2)24
OH
HO
OH
N
O
O
Chelidonic acid (1, 20.0 g, 0.109 mol) was added to 100 mL of 10% aqueous ammonia
and the solution was heated on an oil bath at 95 oC for 4 h with stirring then evaporated to
dryness in vacuo. The resultant residue was dissolved in 100 mL of water and heated to a
boil with stirring. Sufficient conc. HCl (approx. 30 mL) was added to the solution to the
point of precipitation of the product. The solution was allowed to cool, and the precipitate
isolated by filtration then dried to constant mass in an oven to yield chelidamic acid (18.7
g, 95%) as an off-white solid, mp. 263-265 oC (lit. 267 oC).24
1
H NMR (d6-DMSO, 400 MHz.): δ= 7.56 (H; s, 2H); 3.81 (H; s, 3H) ppm
13
C NMR (d6-DMSO, 100 MHz.): δ= 167.2, 165.8, 149.8, 115.3 ppm
IR (ATR): 3109 (aryl C-H stretch); 2833 (O-H stretch, broad); 1648 (C=O stretch) cm-1
22 Diethyl 4-bromo-2,6-pyridinedicarboxylate (3)25
Br
O
O
N
O
O
Phosphorus tribromide (33.7 mL, 0.35 mol) was added to a vigorously stirred solution of
15.3 mL of bromine in 100 mL of petroleum ether. After stirring for a few minutes at
room temperature, the resultant bright yellow PBr5 was washed several times with
petroleum ether by decantation and dried in vacuo. Chelidamic acid (2, 20.0 g, 0.099
mol) was added to the same reaction vessel and thoroughly mixed at room temperature.
The mixture was heated at 90 oC for 3 h then cooled to room temperature. The solution
was stirred with 150 mL chloroform and filtered. Absolute ethanol (400 mL) was added
to the filtrate in small portions to quench the diacyl bromide, the resultant solution was
concentrated in vacuo, and allowed to stand overnight at 4 oC. The crude crystalline
material was recrystallized from hexane (decantation of the hexane solution from
insoluble material was required), to yield a white solid, 3 (14.6 g, 46%), m.p. 95-96 oC
(lit. 95-96 oC).25
1
H NMR (CDCl3, 400 MHz.): δ= 8.41 (H; s, 2H); 4.47 (H; q, J = 6.9 Hz, 4H); 1.44 (H; t,
J = 6.8 Hz, 6H) ppm
13
C NMR (CDCl3, 100 MHz.): δ= 163.6, 149.6, 135.0, 131.2, 62.8, 14.3 ppm
IR (ATR): 2978, 2938, 2905, 2870 (C-H asym/sym stretch); 1716 (C=O ester stretch)
cm-1
23 4-bromo-2,6-pyridinedimethanol (4)26
Br
N
OH
OH
Sodium borohydride (3.42 g, 0.090 mol) was added slowly to a suspension of diester 3
(6.04 g, 0.020 mol) in 250 mL of absolute ethanol over a period of 0.5 h. The mixture
was stirred at room temperature for 2 h, heated under reflux for 15 h, and the solvent
removed in vacuo. Saturated NaHCO3 (32 mL) was added to the residue and the mixture
brought to a boil. Water (45 mL) was added and the mixture was cooled and allowed to
stand overnight in the cold. The resulting mixture was filtered and the filtrate extracted
with chloroform (5 x 70 mL). The combined extracts were dried over sodium sulfate,
and the solvent removed in vacuo. The resultant solid was combined with the residue of
the initial filtration in a soxhlet cup and continuously extracted for 24 h with acetone.
The acetone solution was concentrated and a precipitate formed.
The product was
recrystallized from acetone to yield white crystals of 4 (2.99 g, 68%), m.p. 158-160 oC
(lit. 162-164 oC).26
1
H NMR (d6-DMSO, 400 MHz.): δ= 7.52 (H; s, 2H); 5.54 (H; t, J = 6.0 Hz, 2H); 4.52 (H;
d, J = 5.8 Hz, 4H) ppm
13
C NMR (d6-DMSO, 100 MHz.): δ= 163.8, 133.8, 121.6, 64.2 ppm
IR (ATR): 3344 (O-H stretch); 3094 (aryl C-H stretch) cm-1
24 4-Bromo-2,6-bis(bromomethyl)pyridine (5)26
Br
N
Br
Br
Phosphorous tribromide (1.625 mL, 0.017 mol) was added in one portion to a suspension
of diol 4 (2.32 g, 0.01 mol) in 110 mL of chloroform and the resultant mixture heated
under reflux for 8 hours. The mixture was cooled and neutralized with 5% NaHCO3 and
the chloroform layer was separated. The aqueous layer was extracted with chloroform (6
x 100 mL) and the combined organic extracts were dried over sodium sulfate and the
solvent removed in vacuo. The crude product was recrystallized from a mixture of
hexane and dichloromethane to yield 5 (2.29 g, 63%), as a white solid, m.p. 127-128 oC
(lit 128-129 oC).26
1
H NMR (d6-DMSO, 400 MHz.): δ= 7.81 (H; s, 2H); 4.66 (H; s, 4H) ppm
13
C NMR (d6-DMSO, 100 MHz.): δ= 158.0, 134.3, 126.2, 32.4 ppm
IR (ATR): 3059 (unsaturated ring C-H stretch) cm-1
25 19-bromo-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]-henicosa-1(21),17,19-triene
(6)27-29
O
Br
O
N
O
O
O
Sodium hydride (60% suspension in mineral oil, 355 mg, 2.1 eq.) was added to 500 mL
of THF and stirred at reflux. In a Schlenk flask, tribromide 5 (1.5 g, 4.4 mmol) and
tetraethylene glycol (TEG, 675 µL, 3.9 mmol) was dissolved 60 mL THF. This solution
mixture was transferred to a slow rate addition funnel via cannula, and then added
dropwise over 6 h to the NaH suspension. The reaction was allowed to stir overnight at
room temperature. The solution was filtered by vacuum filtration and the residue washed
with DCM. Solvent was removed from the filtrate in vacuo and the crude product dried
on a high-vacuum line for one hour. Partial purification was achieved by silica gel
column chromatography to yield 6 (48 mg, 2.8%), a yellow oil.
Purification by
preparative TLC (5% methanol: chloroform eluent) yielded additional 6 (297 mg, 17.2%)
as a yellow oil.
1
H NMR (d6-CDCl3, 300 MHz.): δ= 7.41 (H; s, 2H); 4.73 (H; s, 4H); 3.57-3.72 (H; m,
16H) ppm
13
C NMR (d6-CDCl3, 300 MHz.): δ= 159.9, 133.6, 123.7, 73.3, 71.3, 70.7, 70.6, 70.0
ppm
IR (ATR): 2863 (C-H stretch); 1567, 1115 cm-1
26 19-bromo-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]-henicosa-1(21),17,19-triene-21oxide (7)30
O
Br
N
O
O
O
O
O
Crown ether 6 (14 mg, 0.4 mmol) was dissolved in 1mL DCM and cooled to 10 oC with
stirring. 3-Chloroperoxybenzoic acid (1.5 eq) was dissolved in DCM and added to the
solution.
The reaction was stirred at 10 oC for three hours then stirred at room
temperature overnight. The solvent was removed in vacuo. Attempts to separate the
product from m-chlorobenzoic acid by chromatography were unsuccessful.
1
H NMR (d4-MeOH, 400 MHz.): δ= 7.74 (H; s, 2H); 4.86 (H; s, 4H); 3.35-3.85 (H; m,
16H) mixed with m-chlorobenzoic acid: δ= 7.96 (H; dd, J= 1.8, 1.5 Hz, 1H); 7.93 (H;
ddd, J= 7.7, 1.2 Hz, 1H); 7.59 (H; ddd, J= 7.0, 2.2, 1.1 Hz, 1H); 7.45 (H; dd, J= 7.7 Hz,
1H) ppm
13
C NMR (d4-MeOH, 100 MHz.): δ= 151.7, 125.6, 121.0, 71.7, 71.2, 70.7, 70.4, 70.3,
70.2 mixed with m-chlorobenzoic acid: δ= 166.9, 132.7, 132.6, 129.8, 129.2, 127.7 ppm
Chapter 3 – Results and Discussion
3.1
Synthetic Strategies
When considering the synthesis of 4-azido-2,6-pyrido-18-crown-6 N-oxide (6),
the primary disconnection involves the formation of the crown ether ring. The typical
approach involves the use of nucleophilic substitution, and two different synthon
combinations can be employed to generate the target compound (Scheme 12).
Br
O
O
5
A
N
Br
O
N
Br
O
Br
+
O
HO
6
O
O
O
B
Br
+
OH
4
Br
O
O
O
Br
OH
Scheme 12: Retrosynthesis of 2,6-pyrido-18-crown-6 derivative 6
OH
28 One pathway to crown ether 6 would start with a di(bromomethyl)pyridine derivative and
react it with a diol (or its mono- or di-alkoxide, Scheme 12 route A). Alternatively, one
may generate the mono- or di-alkoxide of a pyridine dimethanol, in the presence of a
dihalo or disulfonato polyether derivative obtained from tetraethylene glycol (route B).
Both methods have been successfully used to generate crown ethers in the past.31 4Bromo-2,6-pyridine dimethanol may be considered the common antecedent for both
approaches.
3.2
Synthesis of 4-bromo-2,6-pyridinedimethanol
4-Bromo-2,6-pyridine dimethanol is a synthetically accessible species that may be
prepared in good yield via a simple three-step procedure.
Chelidonic acid (1) is
generated from a Claisen condensation of acetone and 2 molar equivalents of ethyl
oxalate in a two-step process (Scheme 13).
O
O
O
+
O
O
O
O
O
NaOEt
EtOH
CO2Et
EtO2C
H2O
(HCl)
HO2C
O
O
1
O
OH
CO2Et
EtO2C
OH
Scheme 13: Synthesis of Compound 1
CO2H
29 The initial isolable Claisen product was found to exist predominantly as the dienol, rather
than diketo tautomer in chloroform solution. The dienol underwent internal nucleophilic
attack, leading to cyclization to form chelidonic acid, which precipitated from solution in
sufficiently high purity that no additional purification was required. The crude product
was dried in the oven to constant weight to yield 89% of the desired product.
Chelidamic acid (2) is generated from the reaction of 1 and 10% aqueous
ammonia in a one step process (Scheme 14).
O
OH
NH3, HCl/H2O
95oC
HO2C
O
CO2H
HOOC
1
N
2
COOH
Scheme 14: Synthesis of Compound 2
Chelidonic acid undergoes acid catalyzed aminolysis with ammonia to form the desired
dicarboxylic acid. The crude product was precipitated using concentrated HCl and was
dried in the oven to constant weight to remove water. The resulting solid was generated
in good yield (97%) and was used without additional purification.
Diethyl 4-bromo-2,6-pyridinedicarboxylate (3) is generated from the reaction of
chelidamic acid (2) with PBr5, and the resultant dicarbonyl bromide quenched with
absolute ethanol (Scheme 15, overleaf).
30 Br
OH
1. PBr5, pet. ether
2. abs. EtOH
HOOC
N
2
N
3
EtOOC
COOH
COOEt
Scheme 15: Synthesis of diester 3
Phosphorus pentabromide was generated by the reaction of phosphorus tribromide with
bromine, and used directly without any additional purification. This is an SNAr reaction,
favored by the conversion of hydroxide to a dibromophosphite leaving group by reaction
with PBr5. The formed diacyl bromide is readily quenched in ethanol to yield the diester.
The crude product was recrystallized from hexanes to produce white crystals (46% yield).
4-Bromo-2,6-pyridinedimethanol (4) is generated from the reaction of 3 with
sodium borohydride in absolute ethanol (Scheme 16).
Br
Br
1. NaBH4, EtOH
2. Na2CO3/ H2O
EtOOC
N
N
COOEt
3
OH
OH
4
Scheme 16: Synthesis of diol 4
In general, sodium borohydride is not considered a sufficiently strong reducing agent for
carboxylic esters, but cases of successful reduction of aryl and pyridyl esters to primary
alcohols have been reported.32 The product was isolated from the crude crystalline
31 precipitate by continuous (soxhlet) extraction with acetone over 24 hours. White crystals
of compound 4 precipitated out of solution upon concentration in 68% yield.
3.3
Synthesis of Tribromide 5
At this point in the synthesis, the generation of crown ether 6 can proceed via two
different methods.
The pyridinedimethanol, 4, may be reacted with a dihalo or
disulfonato polyether derivative of tetraethylene glycol to generate 6. The other option is
to react a dibromomethylpyridine with tetraethylene glycol to generate 6 (see Scheme 12,
above). In this synthesis, the di(halomethyl)pyridine/tetraethylene glycol method was
used due to the availability of published methods with good reported yields.25,26,28
Benzylic bromination is preferred, as bromide represents a better leaving group than
chloride, and is less susceptible to hydrolysis than the alternative sulfonate esters.
4-Bromo-2,6-bis(bromomethyl)pyridine (5) is generated from the reaction of diol
4 and PBr3 in a one step process (Scheme 17).
Br
Br
PBr3, CHCl3
N
OH
N
Br
OH
4
Br
5
Scheme 17: Synthesis of tribromide 5
In a manner similar in outcome to the reaction utilized to generate 3, bromo groups are
replacing hydroxyl groups.
However, the reaction is mechanistically distinct, as it
32 proceeds via a SN2 mechanism. Phosphorus tribromide is used to convert the alcohols
into dibromophosphites, a better leaving group for SN2 reactions. The crude product was
recrystallized from a mixture of DCM/hexanes (1:1) to yield 63% of the desired product.
3.4
Synthesis of Crown Ether 6
There are a number of procedures utilized in the literature for the synthesis of
species structurally similar to 6,27-29 and all generally follow variations of a central theme:
The alkoxide of the polyether diol is generated in situ with sodium hydride (considered a
strong, non-nucleophilic base), and is allowed to react with the di- (or in this case tri-)
bromide under high dilution conditions (Scheme 18). Typically such reactions proceed in
low to moderate yields. A number of approaches to the synthesis of 6 were attempted:
Br
O
NaH, THF
N
Br
5
0 oC or reflux
Br
N
O
O
O
Br
+
HO
O
O
O
O
OH
6
Scheme 18: Attempted syntheses of crown ether 6
The initial attempt was based on the procedure of Uiterwijk et al.,27 whereby
anhydrous THF solutions of tetraethylene glycol (TEG) and 5 were separately added
33 dropwise to a mixture of NaH and anhydrous THF under reflux conditions. In this
attempt a large excess of base (6.8 eq.) was inadvertently used. 8.75% of the desired
product was formed, in contrast to literature yields of 55% for an analog compound, and
15-37% for differently sized crowns. Loss of yield for 6 was in all likelihood due to the
non-optimal conditions used.
An alternative procedure, published by Tahri, et al.,28 was considered, since this
procedure utilized milder conditions (reaction was carried out at 0oC instead of under
reflux conditions). In addition, a THF solution of 5 was added dropwise to an equilibrated
mixture of TEG and sodium hydride in THF. Based on the stoichiometry, two equivalents
of base would be expected to deprotonate both sides of the glycol, but reported analog
products were generated from 1.1 equivalents of base.28 The usage of more than a single
equivalent of base in these reactions was investigated:
Reaction with large excesses of NaH (8 & 16 molar equivalents respectively) was
unsuccessful.
1
H NMR analysis of crude product mixtures gave little indication of
formation of the desired product, consistent with previous observations.
An alternative possibility considered was to allow reaction to proceed as
published with 1.1 equiv. of sodium hydride, then adding a second equivalent of base to
more closely approach the stoichiometric requirements of reaction. It was considered
important that the bases used should be as non-nucleophilic as possible, to avoid
competing substitution reactions. The bases considered were:
•
Additional sodium hydride: 1.65 and 2 molar equiv. of NaH were used. In the
case where 2 mol. equiv. NaH were used, 1.1 equiv. were used during the initial
reaction and an additional 0.9 equiv. added at 0 oC after stirring overnight.
34 Purification of the crude products was achieved using radial chromatography to
yield 27% (1.65 equiv. NaH) and 18% (2.0 equiv. NaH).
•
N,N-Diisopropylethylamine (Hünig’s base, 1 equiv.),
•
pyridine (1 equiv.), and
•
Na2CO3 (4 equiv.). The larger excess of this particular base was used to offset its
lower solubility in organic solvents.
NMR and TLC analysis of the crude products were inconclusive and the three
bases didn’t seem to provide a better alternative to NaH. Although the three bases
provided milder options to a second equivalent of NaH, there were clear downsides
related to solubility, nucleophilicity and base strength to consider.
Additional concerns regarding the water content in the anhydrous THF solvent,
and the hygroscopicity of TEG became apparent as the study proceeded; attempts to
duplicate the sodium hydride reactions described above were unsuccessful.
It was
necessary to remove the absorbed water from TEG, and this was achieved by fractional
distillation of the material in vacuo. The distillate was subsequently stored over 3Å
molecular sieves in an argon atmosphere.
A third alternative method, published by Storhoff et al.,29 was attempted. This
method involves the dropwise addition of a solution of both 5 and freshly distilled TEG
in THF to a mixture of NaH (2.1 equivalents) in THF under reflux conditions; via a slow
addition dropping funnel. This procedure gave 6 in 20% yield.
Analysis of the product yields indicates that the highest yields were generated
with 1.1-2.1 equiv. of sodium hydride. Alternative bases were not successful, nor was
the use of large excesses of base. Water absorption by TEG, makes it difficult to directly
35 compare many of the attempts to generate 6, since any water in the system will quench
NaH and lead to a lowering of the yield.
The characteristics of a successful reaction
involve using freshly distilled TEG and 2 equiv. of sodium hydride base gives yields
comparable to those in the literature for analog compounds.
3.5
Synthesis of Compound 7
There are a number of procedures utilized in the literature for the oxidation of
pyridine moieties to form N-oxides (Scheme 19).30,35,36 These species are known to
undergo nucleophilic substitution reactions with reasonable facility.
O
O
N
Br
O
O
O
[O]
N
Br
O
O
O
O
O
6
[O] =
O
7
O
O
OH
Cl
O
OH
O
peracetic acid
O
O
dimethyldioxirane
3-chloroperoxybenzoic acid
Scheme 19: Attempted Syntheses of N-oxide 7
Oxidation of crown ether 6 to form the corresponding N-oxide (7) was attempted
using peracetic acid, according to literature procedure.35 Compound 6 was added to a
mixture of glacial acetic acid and 30% w/v hydrogen peroxide and stirred for 3 h at 75
o
C. A second aliquot of 30% w/v hydrogen peroxide was added and heated for an
36 additional 3 h. NMR analysis of the crude product did not give any indication that
oxidation had taken place.
Oxidation utilizing the oxidizing agent 3-chloroperoxybenzoic acid (mchloroperbenzoic acid or mCPBA) was also attempted according to Pentimalli.30 mCPBA
(1.5 eq.) was added to a solution of 6 in dichloromethane at 10 oC. A byproduct of the
reaction, 3-chlorobenzoic acid, proved difficult to separate due to similar retention times
in a variety of different eluents. Extraction with saturated NaHCO3 was unsuccessful and
resulted in reduced yield and did not entirely remove the acid.
The 1H NMR spectrum of the reaction mixture was consistent with the oxidation
of the pyridine ring to form an N-oxide in comparison with the spectrum of the starting
material, 6 (Figure 5, overleaf).
A shift in peaks at the 3-position on the pyridine ring and the crown ether protons
indicates oxidation has occurred and can be supported when compared to the analogous
compounds, 2,6-dimethylpyridine and 2,6-dimethylpyridine 1-oxide and their shift in
peaks downfield with oxidation.33,34 The NMR spectra of these species indicate changes
in chemical shifts for protons at the 3-position from 6.9 to 7.5 ppm upon oxidation, and
benzylic proton chemical shifts change from 2.5 to 2.6 ppm. The crude spectrum of 7
shows a similar change in chemical shift: 7.41 to 7.64, 4.73 to 4.96 ppm. The 3chlorobenzoic acid byproduct is still present in the sample, and has resonances at 8.03,
7.92, 7.51, and 7.35 ppm.
37 9.0
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Figure 5: NMR Comparison of crown ether 6 (top) & N-oxide 7 (m-chlorobenzoic acid
peaks denoted with ⊗ )
An alternative method for oxidation of pyridines to pyridine N-oxides involved
the use of dimethyldioxirane (DMD) as the oxidizing agent.36 Since the product of the
reaction is acetone, this procedure should provide greater ease of separation of the
reduced product away from the desired product. Access to commercially available DMD
was not available so it needed to be prepared.37,38 The reference procedure only produces
R.X+.["A9:((((((()
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R.<7#?$(((((((((()
]%"9"&#.[&"9((((()
P:&?$.<6$?$9((((()
F$5C6.=&"%((((((()
F$#&>&9";%.A$#&^()
H$'<.=$9((((((((()
M%_#&%\.9"'$((((()
38 a 5% yield of DMD in acetone (approximately 0.1 M), and requires rigorous
condensation techniques, due to the volatility of the compound. Synthesis of DMD was
unsuccessful as confirmed by 1H NMR, probably due to inefficient cooling of the
collection apparatus.
3.6
Attempts to Incorporate the Azido- group
In principle, incorporation of the azido-group onto the crown skeleton could be
performed prior to, or after oxidation of the pyridine ring. The azido group is relatively
inert toward most standard oxidants. Oxidation of organic azides has been reported under
forcing conditions, using hypofluorous acid as an oxidant.39
Initial attempts were carried out using the crude N-oxide generated from the
mCPBA reactions (Scheme 20).
O
Br
N
O
O
O
O
O
NaN3, 95% EtOH
N3
O
N
O
O
O
O
O
8
7
Scheme 20: Attempted synthesis of target compound 8
Sodium azide (2 equiv.) was added to a mixture of 6 in 95% ethanol. IR analysis of the
crude product indicated the presence of an azide, but it was inconclusive whether it was
the desired product or residual unreacted sodium azide.
39 Alternatively, azide functionalization was attempted on crown ether 6 before
oxidation (Scheme 21).
O
Br
O
N
O
O
O
NaN3, 95% EtOH
N3
O
O
N
O
O
6
O
9
Scheme 21: Synthesis of 19-azido-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]-henicosa1(21),17,19-triene (9)
Sodium azide (1.5 equiv.) was added to a mixture of 6 in 95% ethanol. 1H NMR of the
product mixture did show some evidence of changes of chemical shifts relative to the
starting material. However, it was not clear whether these shifts arose from incorporation
of the azide group, or through complexation of sodium by the crown. Analysis of the
FTIR spectrum of the isolated material (isolated by filtration, and solvent removed in
vacuo over 24 h) is similarly equivocal. The FTIR shows peaks at 2112 and 2022 cm-1.
The former (a relatively low intensity peak) is consistent with the formation of an aryl
azide. The latter peak is not, but neither is it consistent with the solid state spectrum of
sodium azide, which also has peak absorption around 2120 cm-1 (in paraffin mull).
Additional study of this reaction is clearly required.
Further study and improvements in the synthesis and purification of 7 and 8 are
necessary to obtain the desired 4-azido-2,6-pyrido-18-crown-6 N-oxide product. Since
purification of 7 from 3-chlorobenzoic acid proved difficult, new methods could be
40 utilized such as preparative LC or HPLC. Also, the preparation of dimethyldioxirane
(DMD) could be improved by improving the efficiency of the cooling apparatus. With
successful generation of DMD, a new, easier to purify, method of oxidation can be
utilized. From the purification of 7, the incorporation of an azido- group can be further
studied. Successful generation of 8 can be used in future metal cation complexation and
nitrene reactivity studies.
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(1)
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(2)
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(3)
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(9)
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(13)
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(14)
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(39)
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44 Appendices – Table of Contents
Appendix A – Experimental Spectra
A.1
A.2
A.3
A.4
A.5
A.6
A.7
A.8
diethyl 2,4-dioxopentanedioate
A.1.1 IR (ATR)
4-oxo-4H-pyran-2,6-dicarboxylic acid (1)
A.2.1 1H NMR (in d6-DMSO)
A.2.2 13C NMR (in d6-DMSO)
A.2.3 IR (ATR)
4-hydroxy-2,6-pyridinedicarboxylic acid (2)
A.3.1 1H NMR (in d6-DMSO)
A.3.2 13C NMR (in d6-DMSO)
A.3.3 IR (ATR)
diethyl 4-bromo-2,6-pyridinedicarboxylate (3)
A.4.1 1H NMR (in CDCl3)
A.4.2 13C NMR (in CDCl3)
A.4.3 IR (ATR)
4-bromo-2,6-pyridinedimethanol (4)
A.5.1 1H NMR (in d6-DMSO)
A.5.2 13C NMR (in d6-DMSO)
A.5.3 IR (ATR)
4-bromo-2,6-bis(bromomethyl)pyridine (5)
A.6.1 1H NMR (in d6-DMSO)
A.6.2 13C NMR (in d6-DMSO)
A.6.3 IR (ATR)
19-bromo-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]-henicosa-1(21),17,19triene (6)
A.7.1 1H NMR (in CDCl3)
A.7.2 13C NMR (in CDCl3)
A.7.3 IR (ATR)
19-bromo-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]-henicosa-1(21),17,19triene-21-oxide (7)
A.8.1 1H NMR (in d4-MeOH)
A.8.2 13C NMR (in d4-MeOH)
45 A.1.1 Compound 0 – IR
I
N
CO2Et
\o
t!
ci
6
ta
!
a
!
EtO2C
\o
o\
t\
O
()
O
oo
O
\o
6
a
GI
ra
6l
O\
C
6u.)
O
O\
!.-) 9
t\
F
ql
\Ct e
6
r.l
ti
O
6
F
rn
<
A
v.)
O
ra
O
C-
30.0
20.0
10.0
0
10.0
8.0
X : parts per Million : 1H
9.0
7.0
6.9590
6.0
5.0
4.0
3.0
HO
1.92
2.5107
2.5062
2.5025
O
2.0
O
O
1.0
O
OH
0
M.V*.Y"@89((((((()(-->,Q6=
M.&3X.8"'$((((((()(A>IO-AM.&%;#$(((((((((()(+,Q@$;R
M.56#=$(((((((((()(,>I,Q6=
[%"8"&#.Y&"8((((()(-Q=R
G9&=$.5:$=$8((((()(OQ6=R
H$3B:.;&"%((((((()(-V
H$#&<&8"4%.@$#&\()(+Q=R
T$'5.;$8((((((((()(AA>VQ@F
]%^#&%Z.8"'$((((()(AQ6=R
!"$#@.=8:$%;89((()(V>OPVIE
M.&3X.@6:&8"4%((()(A>IO-AM.@4'&"%((((((((()(-2
M.K:$X((((((((((()(OVV>IPA
M.4KK=$8((((((((()(,Q55'R
M.54"%8=((((((((()(-EOP+
M.5:$=3&%=((((((()(*
M.:$=4#68"4%((((()(*>OEE-O
M.=Y$$5(((((((((()(,>VVPP*
F#"55$@(((((((((()(!7L?0
/4@.:$86:%((((((()(?3&%=(((((((((((()(-E
T48&#.=3&%=(((((()(-E
F4''$%8(((((((((()(?"%;#$(
C&8&.K4:'&8(((((()(-C(FD/G
C"'.="N$((((((((()(-EOP+
C"'.8"8#$(((((((()(-2
C"'.6%"8=(((((((()(Q55'R
C"'$%="4%=((((((()(M
?"8$((((((((((((()(03#"5=$
?5$38:4'$8$:((((()(C0LT7.U
!"#$%&'$((((((((()(*+*,-*.
76894:((((((((((()(544#$;:
0<5$:"'$%8((((((()(="%;#$.
?&'5#$."@(((((((()(34'546%
?4#B$%8(((((((((()(C/?D!CE
F:$&8"4%.8"'$(((()((,!7GH!
H$B"="4%.8"'$(((()((,!7GH!
F6::$%8.8"'$((((()((,!7GH!
A.2.1 Compound 1 – 1H
46 1
(Millions)
179.7722
160.0
X : parts per Million : 13C
170.0
161.2821
180.0
150.0
154.4993
200.0190.0
140.0
130.0
120.0
119.4001
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
110.0
HO
100.0
O
90.0
O
O
80.0
70.0
O
OH
60.0
50.0
40.0
40.2855
40.0791
39.8650
30.0
20.0
10.0
O.V*.K"?9:((((((()(A*WVQ7>R
O.&4Z.9"'$((((((()(-W2**JJV
O.&%<#$(((((((((()(2*Q?$<R
O.67#>$(((((((((()(EWVEEEEE
\%"9"&#.K&"9((((()(-Q>R
F:&>$.6;$>$9((((()(2Q7>R
G$4B;.<&"%((((((()(AJ
G$#&=&9"5%.?$#&]()(-Q>R
T$'6.<$9((((((((()(A+WEQ?3R
^%_#&%[.9"'$((((()(AQ7>R
!"$#?.>9;$%<9:((()(VW2JVHEE
O.&4Z.?7;&9"5%((()(-W2**JJV
O.?5'&"%((((((((()(-23
O.M;$Z((((((((((()(-**W,A,2
O.5MM>$9((((((((()(-**Q66'R
O.65"%9>((((((((()(2AHEJ
O.6;$>4&%>((((((()(+
O.;$>5#79"5%((((()(*WHEJH*+
O.>K$$6(((((((((()(A,W-JJV\;;.?5'&"%((((((()(-Y
\;;.M;$Z((((((((()(2VVWHJA\;;.5MM>$9((((((()(,Q66'R
3#"66$?(((((((((()(!8N@0
/5?.;$97;%((((((()(@4&%>(((((((((((()(J+E
T59&#.>4&%>(((((()(J+E
35''$%9(((((((((()(@"%<#$(F
C&9&.M5;'&9(((((()(-C(3D/FN
C"'.>"P$((((((((()(2AHEJ
C"'.9"9#$(((((((()(-23
C"'.7%"9>(((((((()(Q66'R
C"'$%>"5%>((((((()(O
@"9$((((((((((((()(04#"6>$(
@6$49;5'$9$;((((()(C0NT8.U/
!"#$%&'$((((((((()(*+*,-*./
879:5;((((((((((()(655#$<;6
0=6$;"'$%9((((((()(>"%<#$.6
@&'6#$."?(((((((()(45'657%?
@5#B$%9(((((((((()(C/@D!CE
3;$&9"5%.9"'$(((()((,!8FG!A
G$B">"5%.9"'$(((()((,!8FG!A
37;;$%9.9"'$((((()((,!8FG!A
A.2.2 Compound 1 – 13C
47 (Millions)
48 A.2.3 Compound 1 – IR
1
<>
\o
c
F
<i
6
a
t.l
n
\o
\o o\
!f
o
c.l
t
q
F
o\
o\
<f,
c.l
el
o\
dl
i+
F
=l
N!+
F
-d;\o
CL
ttt
t,o.
E
(J
_l
OH
;,
o
O
cl
6
6lh
E
I
ro
(o
E
O
O
o
o
o
CL
O
an
(!
(!
!t
_l
(,
HO
o.
ii
i
o\oornor.l<>ro'.loi.loN
OO\O\!oOt*t\\c)\Oinr.}=f,$F
Ocn
i-
1O
o\
5.0
4.0
3.0
2.0
1.0
10.0
8.0
X : parts per Million : 1H
9.0
7.0
HO
O
6.0
N
OH
5.0
O
OH
4.0
3.0
3.56
2.5052
0
2.0
1.0
0
P.K*.Y"@89((((((()(-->,R6=
P.&3X.8"'$((((((()(A>IL-AP.&%;#$(((((((((()(+,R@$;S
P.56#=$(((((((((()(,>I,R6=
[%"8"&#.Y&"8((((()(-R=S
G9&=$.5:$=$8((((()(LR6=S
H$3B:.;&"%((((((()(-M
H$#&<&8"4%.@$#&\()(+R=S
U$'5.;$8((((((((()(AL>AR@F
]%^#&%Z.8"'$((((()(AR6=S
!"$#@.=8:$%;89((()(K>LMKIE
P.&3X.@6:&8"4%((()(A>IL-AP.@4'&"%((((((((()(-2
P.N:$X((((((((((()(LKK>IMA
P.4NN=$8((((((((()(,R55'S
P.54"%8=((((((((()(-ELM+
P.5:$=3&%=((((((()(*
P.:$=4#68"4%((((()(*>LEE-L
P.=Y$$5(((((((((()(,>KKMM*
F#"55$@(((((((((()(!7O?0
/4@.:$86:%((((((()(?3&%=(((((((((((()(-E
U48&#.=3&%=(((((()(-E
F4''$%8(((((((((()(?"%;#$(
C&8&.N4:'&8(((((()(-C(FD/G
C"'.="Q$((((((((()(-ELM+
C"'.8"8#$(((((((()(-2
C"'.6%"8=(((((((()(R55'S
C"'$%="4%=((((((()(P
?"8$((((((((((((()(03#"5=$
?5$38:4'$8$:((((()(C0OU7.V
!"#$%&'$((((((((()(*+*,-*.
76894:((((((((((()(544#$;:
0<5$:"'$%8((((((()(="%;#$.
?&'5#$."@(((((((()(34'546%
?4#B$%8(((((((((()(C/?D!CE
F:$&8"4%.8"'$(((()((,!7GH!
H$B"="4%.8"'$(((()((,!7GH!
F6::$%8.8"'$((((()((,!7GH!
A.3.1 Compound 2 – 1H
49 3.8094
7.5579
0.76
(Millions)
170.0
160.0
X : parts per Million : 13C
180.0
167.1472
165.8320
200.0190.0
150.0
149.7888
140.0
130.0
120.0
110.0
HO
115.2708
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
100.0
O
90.0
N
OH
80.0
O
70.0
OH
60.0
50.0
40.0
40.0791
30.0
20.0
10.0
0
N.V*.J"?9:((((((()(A*WVQ7>R
N.&4Z.9"'$((((((()(-W2**IIV
N.&%<#$(((((((((()(2*Q?$<R
N.67#>$(((((((((()(EWVEEEEE
\%"9"&#.J&"9((((()(-Q>R
F:&>$.6;$>$9((((()(2Q7>R
G$4B;.<&"%((((((()(AI
G$#&=&9"5%.?$#&]()(-Q>R
T$'6.<$9((((((((()(A+W,Q?3R
^%_#&%[.9"'$((((()(AQ7>R
!"$#?.>9;$%<9:((()(VW2IVPEE
N.&4Z.?7;&9"5%((()(-W2**IIV
N.?5'&"%((((((((()(-23
N.L;$Z((((((((((()(-**W,A,2
N.5LL>$9((((((((()(-**Q66'R
N.65"%9>((((((((()(2APEI
N.6;$>4&%>((((((()(+
N.;$>5#79"5%((((()(*WPEIP*+
N.>J$$6(((((((((()(A,W-IIV\;;.?5'&"%((((((()(-Y
\;;.L;$Z((((((((()(2VVWPIA\;;.5LL>$9((((((()(,Q66'R
3#"66$?(((((((((()(!8M@0
/5?.;$97;%((((((()(@4&%>(((((((((((()(A****
T59&#.>4&%>(((((()(A****
35''$%9(((((((((()(@"%<#$(F
C&9&.L5;'&9(((((()(-C(3D/FM
C"'.>"O$((((((((()(2APEI
C"'.9"9#$(((((((()(-23
C"'.7%"9>(((((((()(Q66'R
C"'$%>"5%>((((((()(N
@"9$((((((((((((()(04#"6>$(
@6$49;5'$9$;((((()(C0MT8.U/
!"#$%&'$((((((((()(*+*,-*./
879:5;((((((((((()(655#$<;6
0=6$;"'$%9((((((()(>"%<#$.6
@&'6#$."?(((((((()(45'657%?
@5#B$%9(((((((((()(C/@D!CE
3;$&9"5%.9"'$(((()((E!8FG!A
G$B">"5%.9"'$(((()((E!8FG!A
37;;$%9.9"'$((((()((E!8FG!A
A.3.2 Compound 2 – 13C
50 (Millions)
51 A.3.3 Compound 2 – IR
m
q
\o
ho\
+
6l
o\
tf
N
tt
\6
N
$
s
r+
,1
nq
6
c!
o
6l
t\ F
dl
4t
$
F
o
q
!tCL
OH
ot
E
o
.;l
O
it
o
rl)
(o
(l
N
OH
E,
g
.J
o
c\
c!
Gq
!
c
\o
F
t
n
(a
!ia
o(
o\
1,
o
HO
oo
ta
a!
a!
O
\C}
IU
I
raora
ria!'.
o\
$
0.31
X : parts per Million : 1H
8.0
17.17m
8.4120
8.2512
30.0
20.0
10.0
0
O
7.0
68.06m
7.2530
O
6.0
N
Br
O
O
5.0
0.68
4.4899
4.4725
4.4542
4.0
3.0
2.0
85.98m
1.8078
1.4612
1.4438
1.4255
1.0
0
N.L*.Y"@89((((((()(-->JR6=
N.&3X.8"'$((((((()(,>KA-,N.&%;#$(((((((((()(+JR@$;S
N.56#=$(((((((((()(J>KJR6=
[%"8"&#.Y&"8((((()(-R=S
H9&=$.5:$=$8((((()(AR6=S
F$3B:.;&"%((((((()(-K
F$#&<&8"4%.@$#&\()(+R=S
U$'5.;$8((((((((()(,AR@CS
]%^#&%Z.8"'$((((()(,R6=S
!"$#@.=8:$%;89((()(L>AQLKP
N.&3X.@6:&8"4%((()(,>KA-,N.@4'&"%((((((((()(-2
N.M:$X((((((((((()(ALL>KQ,
N.4MM=$8((((((((()(JR55'S
N.54"%8=((((((((()(-PAQ+
N.5:$=3&%=((((((()(*
N.:$=4#68"4%((((()(*>APP-A
N.=Y$$5(((((((((()(J>LLQQ*
C#"55$@(((((((((()(!7D?0
/4@.:$86:%((((((()(?3&%=(((((((((((()(Q
U48&#.=3&%=(((((()(Q
C4''$%8(((((((((()(?"%;#$(
G&8&.M4:'&8(((((()(-G(CE/H
G"'.="O$((((((((()(-PAQ+
G"'.8"8#$(((((((()(-2
G"'.6%"8=(((((((()(R55'S
G"'$%="4%=((((((()(N
?"8$((((((((((((()(03#"5=$
?5$38:4'$8$:((((()(G0DU7.V
!"#$%&'$((((((((()(*+*,-*.
76894:((((((((((()(544#$;:
0<5$:"'$%8((((((()(="%;#$.
?&'5#$."@(((((((()(34'546%
?4#B$%8(((((((((()(C2DEFE!
C:$&8"4%.8"'$(((()((,!7HF!
F$B"="4%.8"'$(((()((J!7HF!
C6::$%8.8"'$((((()((J!7HF!
A.4.1 Compound 3 – 1H
52 1.0
(Millions)
180.0
170.0
160.0
X : parts per Million : 13C
200.0190.0
150.0
149.5824
O
163.6220
N
140.0
O
130.0
O
135.0227
131.1610
O
120.0
110.0
100.0
90.0
80.0
70.0
77.4264
77.1052
76.7841
4.0
3.0
2.0
1.0
0
Br
60.0
62.8209
50.0
40.0
30.0
20.0
10.0
14.2785
0
Q.I*.N"?9:((((((()(,*XIS7>
Q.&4Z.9"'$((((((()(-X2**MM
Q.&%<#$(((((((((()(2*S?$<T
Q.67#>$(((((((((()(JXIJJJJ
\%"9"&#.N&"9((((()(-S>T
G:&>$.6;$>$9((((()(2S7>T
E$4A;.<&"%((((((()(,I
E$#&=&9"5%.?$#&]()(-S>T
V$'6.<$9((((((((()(,+XJS?3
^%_#&%[.9"'$((((()(,S7>T
!"$#?.>9;$%<9:((()(IX2MILJ
Q.&4Z.?7;&9"5%((()(-X2**MM
Q.?5'&"%((((((((()(-23
Q.P;$Z((((((((((()(-**XK,K
Q.5PP>$9((((((((()(-**S66'
Q.65"%9>((((((((()(2,LJM
Q.6;$>4&%>((((((()(+
Q.;$>5#79"5%((((()(*XLJML*
Q.>N$$6(((((((((()(,KX-MMI
\;;.?5'&"%((((((()(-B
\;;.P;$Z((((((((()(2IIXLM,
\;;.5PP>$9((((((()(KS66'T
3#"66$?(((((((((()(!8C@0
/5?.;$97;%((((((()(@4&%>(((((((((((()(-+I
V59&#.>4&%>(((((()(-+I
35''$%9(((((((((()(@"%<#$(
F&9&.P5;'&9(((((()(-F(3D/G
F"'.>"R$((((((((()(2,LJM
F"'.9"9#$(((((((()(-23
F"'.7%"9>(((((((()(S66'T
F"'$%>"5%>((((((()(Q
@"9$((((((((((((()(04#"6>$
@6$49;5'$9$;((((()(F0CV8.W
!"#$%&'$((((((((()(*+*,-*.
879:5;((((((((((()(655#$<;
0=6$;"'$%9((((((()(>"%<#$.
@&'6#$."?(((((((()(45'657%
@5#A$%9(((((((((()(3BCDED!
3;$&9"5%.9"'$(((()((,!8GE!
E$A">"5%.9"'$(((()((K!8GE!
37;;$%9.9"'$((((()((K!8GE!
A.4.2 Compound 3 – 13C
53 (Millions)
54 A.4.3 Compound 3 – IR
th
o
cl
!o
\o
al
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\o
.i
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lo\
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9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
7.5158
0.492
X : parts per Million : 1H
7.0
6.0
5.0
1
4.5320
4.5174
0.51
5.5550
5.5403
5.5248
4.0
OH
N
3.0
Br
OH
R.Y*.]"589((((((()(--?KU7>
R.&3\.8"'$((((((()(,?ZO-,R.&%<#$(((((((((()(+KU5$<V
R.47#>$(((((((((()(K?ZKU7>
_%"8"&#.]&"8((((()(-U>V
H9&>$.4;$>$8((((()(OU7>V
I$3D;.<&"%((((((()(-G
I$#&=&8":%.5$#&`()(+U>V
X$'4.<$8((((((((()(,O?-U5A
M%C#&%^.8"'$((((()(,U7>V
!"$#5.>8;$%<89((()(Y?OTYZG
R.&3\.57;&8":%((()(,?ZO-,R.5:'&"%((((((((()(-2
R.P;$\((((((((((()(OYY?ZT,
R.:PP>$8((((((((()(KU44'V
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R.;$>:#78":%((((()(*?OGG-O
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A#"44$5(((((((((()(!6Q@0
/:5.;$87;%((((((()(@3&%>(((((((((((()(T
X:8&#.>3&%>(((((()(T
A:%8$%8(((((((((()(@"%<#$(
E&8&.P:;'&8(((((()(-E(AF/H
E"'.>"S$((((((((()(-GOT+
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E"'.7%"8>(((((((()(U44'V
E"'$%>":%>((((((()(R
@"8$((((((((((((()(03#"4>$
@4$38;:'$8$;((((()(E0QX6.N
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6789:;((((((((((()(4::#$<;
0=4$;"'$%8((((((()(>"%<#$.
@&'4#$."5(((((((()(A:'4:7%
@:#D$%8(((((((((()(E/@F!EG
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I$D">":%.8"'$(((()((G!LMN!
A7;;$%8.8"'$((((()((G!LMN!
A.5.1 Compound 4 – 1H
55 (Millions)
160.0
150.0
X : parts per Million : 13C
180.0 170.0
OH
163.7979
N
140.0
OH
130.0
133.8069
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
Br
120.0
121.6177
110.0
100.0
90.0
80.0
70.0
60.0
64.2126
50.0
40.0
30.0
20.0
10.0
0
P.K*.L"69:((((((()(,*XKS8?
P.&4[.9"'$((((((()(-X2**RR
P.&%=#$(((((((((()(2*S6$=T
P.58#?$(((((((((()(EXKEEEE
]%"9"&#.L&"9((((()(-S?T
F:&?$.5<$?$9((((()(2S8?T
G$4B<.=&"%((((((()(,R
G$#&>&9";%.6$#&^()(-S?T
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_%A#&%\.9"'$((((()(,S8?T
!"$#6.?9<$%=9:((()(KX2RKJE
P.&4[.68<&9";%((()(-X2**RR
P.6;'&"%((((((((()(-23
P.N<$[((((((((((()(-**XI,I
P.;NN?$9((((((((()(-**S55'
P.5;"%9?((((((((()(2,JER
P.5<$?4&%?((((((()(+
P.<$?;#89";%((((()(*XJERJ*
P.?L$$5(((((((((()(,IX-RRK
]<<.6;'&"%((((((()(-Z
]<<.N<$[((((((((()(2KKXJR,
]<<.;NN?$9((((((()(IS55'T
3#"55$6(((((((((()(!7O@0
/;6.<$98<%((((((()(@4&%?(((((((((((()(-2R
V;9&#.?4&%?(((((()(-2R
3;''$%9(((((((((()(@"%=#$(
C&9&.N;<'&9(((((()(-C(3D/F
C"'.?"Q$((((((((()(2,JER
C"'.9"9#$(((((((()(-23
C"'.8%"9?(((((((()(S55'T
C"'$%?";%?((((((()(P
@"9$((((((((((((()(04#"5?$
@5$49<;'$9$<((((()(C0OV7.W
!"#$%&'$((((((((()(*+,,-*.
789:;<((((((((((()(5;;#$=<
0>5$<"'$%9((((((()(?"%=#$.
@&'5#$."6(((((((()(4;'5;8%
@;#B$%9(((((((((()(C/@D!CE
3<$&9";%.9"'$(((()(,,!7FG!
G$B"?";%.9"'$(((()(,,!7FG!
38<<$%9.9"'$((((()(,,!7FG!
A.5.2 Compound 4 – 13C
56 (Millions)
57 A.5.3 Compound 4 – IR
th
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58 A.6.1 Compound 5 – 1H
!"#$%%$&'()
S.[*./"
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B8<<$%9
170.0
160.0
150.0
X : parts per Million : 13C
158.0092
Br
N
140.0
Br
134.3039
4.0
3.0
2.0
1.0
0
Br
130.0
120.0
110.0
100.0
90.0
80.0
77.4188
77.1052
76.7841
70.0
60.0
50.0
40.0
30.0
32.4398
R.Y*.P"6:;((((((()(,-Z-TU9
R.&4\.:"'$((((((()(,Z2**TT
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A4&%@(((((((((((()(,J+
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3<%:$%:(((((((((()(A"%>#$(
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A.6.2 Compound 5 – 13C
59 126.1829
(Millions)
60 A.6.3 Compound 5 – IR
9
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14.0
13.0
12.0
11.0
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
7.2543
X : parts per Million : 1H
8.0
0.112
7.4091
7.0
Br
6.0
N
O
O
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5.0
4.0
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A.7.1 Compound 6 – 1H
61 3.7227
3.6696
3.6540
3.5807
3.5743
1
0.236
4.7308
(Millions)
160.0
Br
150.0
X : parts per Million : 13C
159.8662
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0
N
140.0
O
O
130.0
O
O
O
120.0
110.0
100.0
90.0
80.0
70.0
73.2579
71.3036
70.7310
70.5631
69.9600
T-]*-Q"@89((((((()(V4+W7?X
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A.7.2 Compound 6 – 13C
62 77.5559
123.6885
133.6433
(Thousands)
63 A.7.3 Compound 6 – IR
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7.0
6.0
5.0
4.0
3.0
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1.0
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68.447m
88.207m
0.166
X : parts per Million : 1H
7.9609
7.9563
7.9142
7.7411
7.5763
7.5735
7.5708
7.4682
7.4490
O
O
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7.0
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6.0
5.0
4.0
0.894
3.5676
3.5475
3.3469
3.3048
3.3011
0.418
4.8819
4.8562
4.7326
4.6978
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Q8&>$-;:$>$5((((()(4V7>W
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C$';-<$5((((((((()(J43LV@HW
P%`#&%]-5"'$((((()(JV7>W
!"$#@->5:$%<58((()(Y34,Y2UUVCW
S-&A[-@7:&5"9%((()(J324*J*J,V>
S-@9'&"%((((((((()(*1
S-R:$[((((((((((()(4YY32,J*Y,4
S-9RR>$5((((((((()(NV;;'W
S-;9"%5>((((((((()(*U4,L
S-;:$>A&%>((((((()(+
S-:$>9#75"9%((((()(+34UU*422*V
S->\$$;(((((((((()(N3YY,,++JLV
H#";;$@(((((((((()(!6F?/
.9@-:$57:%((((((()(*
?A&%>(((((((((((()(,
C95&#->A&%>(((((()(,
H9%5$%5(((((((((()(?"%<#$(Q7#>
G&5&-R9:'&5(((((()(*G(HE.QF/S
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G"'-5"5#$(((((((()(*1
G"'-7%"5>(((((((()(V;;'W
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?"5$((((((((((((()(/A#";>$(X(L
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!"#$%&'$((((((((()(**+,*+-./067589:((((((((((()(;99#$<:;
/=;$:"'$%5((((((()(>"%<#$-;7#>
?&';#$-"@(((((((()(234(A:7@$('
?9#B$%5(((((((((()(./C16DEF!G4
H:$&5"9%-5"'$(((()((,!DEI!J+*+
M$B">"9%-5"'$(((()((N!OPF!J+**
H7::$%5-5"'$((((()((N!OPF!J+**
A.8.1 Compound 7 – 1H
64 3.8598
3.8497
3.8387
(Millions)
166.9255
160.0
150.0
N
X : parts per Million : 13C
170.0
Br
151.7235
2.0
1.0
0
O
O
140.0
130.0
O
O
O
120.0
134.1815
132.7057
132.5604
129.8305
129.2340
127.7199
125.5865
120.9830
O
110.0
100.0
90.0
80.0
70.0
71.7371
71.1560
70.7354
70.3989
60.0
50.0
47.9248
47.7106
47.4965
40.0
U-[+-R"?78((((((()(*343,W6>X
U-&@]-7"'$((((((()(*41++,,[PW
U-&%<#$(((((((((()(1+W?$<X
U-;6#>$(((((((((()(L4[JPPPPP3
_%"7"&#-R&"7((((()(*W>X
Q8&>$-;:$>$7((((()(1W6>X
M$@B:-<&"%((((((()(J,
M$#&=&7"9%-?$#&`()(*W>X
C$';-<$7((((((((()(JLW?2X
O%a#&%^-7"'$((((()(JW6>X
!"$#?->7:$%<78((()([41,[3PPWC
U-&@]-?6:&7"9%((()(*41++,,[PW
U-?9'&"%((((((((()(*12
U-T:$]((((((((((()(*++4LJL1+1
U-9TT>$7((((((((()(*++W;;'X
U-;9"%7>((((((((()(1J3P,
U-;:$>@&%>((((((()(Z
U-:$>9#67"9%((((()(+43P,3+Z3Z
U->R$$;(((((((((()(JL4*,,[*P,
_::-?9'&"%((((((()(*D
_::-T:$]((((((((()(1[[43,J*[,
_::-9TT>$7((((((()(LW;;'X
2#";;$?(((((((((()(!5GA/
.9?-:$76:%((((((()(*
A@&%>(((((((((((()(PP1
C97&#->@&%>(((((()(PP1
29%7$%7(((((((((()(A"%<#$(Q6#
H&7&-T9:'&7(((((()(*H(2F.QG/U
H"'->"V$((((((((()(1J3P,
H"'-7"7#$(((((((()(*12
H"'-6%"7>(((((((()(W;;'X
H"'$%>"9%>((((((()(U
A"7$((((((((((((()(/@#";>$(Y(
A;$@7:9'$7$:((((()(H/GC5-E.M
!"#$%&'$((((((((()(**+,*+-./0
56789:((((((((((()(;99#$<:;
/=;$:"'$%7((((((()(>"%<#$-;6#
A&';#$-"?(((((((()(341(@:6?$(
A9#B$%7(((((((((()(./CD5EFG!H
2:$&7"9%-7"'$(((()((,!EFI!J+*
M$B">"9%-7"'$(((()((L!NOG!J+*
26::$%7-7"'$((((()((L!NOG!J+*
A.8.2 Compound 7 – 13C
65 (Millions)