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Nitration of arylboronic acids

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Nitration of arylboronic acids

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Content NITRATION OF ARYLBORONIC ACIDS
by
Stefan Salzbrunn
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(Chemistry)
August 1999
© 1999 Stefan Salzbrunn
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UN IVE R S ITY O F S O U T H E R N CALIFORNIA
THE GRADUATE SCHOOL
U N IV ER S ITY PARK
LOS ANGELES. C A LIFO R N IA * 0 0 0 7
This thesis, written by
Stefan Salzbrunn
under the direction of hJLs.— Thesis Committee,
and approved by a ll its members, has been pre
sented to and accepted by the Dean of The
Graduate School, in p artial fulfillment of the
requirements fo r the degree of
Master o f Science (C h e a ls try )
D a te ..J " ± y ± iJ i9 .lL ..
THESIS O 0M M ITTEE
/ l
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To my Parents
ii
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ACKNOWLEDGMENTS
I am extremely thankful to Professor G. K. Surya Prakash and Professor
George A. Olah for their support, guidance and supervision at the Loker
Hydrocarbon Research Institute. Their advice and counsel have made this time
very encouraging and enjoyable.
Professor Hans-Ullrich Siehl and his research group are thanked for their
support and collaboration during the stay at USC.
I thank all the coworkers and friends at the Loker Institute for their efforts in
helping each other in all situations. Especially Dr. Jurgen Simon is thanked for his
collaboration efforts and time in teaching me new laboratory techniques and being
a good friend.
Professor Nicos A. Petasis and his research group are thanked for the
collaborative efforts in this research field.
Furthermore, I want to thank my roommate Yuk Yin Sham and his wife for
their friendship and all the fun we had and wish them all the best.
The Konrad Adenauer Foundation and the Fulbright Commission are
thanked for fellowships that have made this stay possible.
Finally, words fall short to express my gratitude to all my family, relatives
and friends for their incredible support during the years. My mother and father, Dr.
and Mrs. Oschmann and Jud Partin are especially thanked.
iii
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TABLE OF CONTENTS
DEDICATION ii
ACKNOWLEDGMENTS iii
LIST OF TABLES AND FIGURES vi
LIST OF SCHEMES vii
ABSTRACT viii
1 General Introduction 1
1.1 Properties and Applications of Arylboronic Acids 1
1.2 Preparation of Arylboronic Acids 4
1.3 Electrophilic /pso-Substitution of Arylboronic Acids 6
1.3.1 Background:/pso-Substitution Reactions 6
1.3.2 /pso-Substitution of Arylboronic Acids 8
1.4 Electrophilic Nitration 9
1.5 Thesis Scope 11
1.6 References 13
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2 Results and Discussion 15
2.1 Regioselective/pso-Nitration 15
2.2 Nitration with Excess Nitrating Agent: Formation
of Dinitro Compounds 20
2.3 Proposed Mechanistic Pathway 26
2.4 Conclusion and Outlook 31
2.5 References 33
3 Experimental 34
3.1 General Aspects 34
3.2 Nitration Reactions 36
3.2.1 General Procedure with Equimolar Nitrating Agent 36
3.2.2 General Procedure with Excess Nitrating Agent 37
3.3 Mononitro Compounds Prepared 37
3.4 Dinitro Compounds Prepared 39
3.5 References 42
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LIST OF TABLES AND FIGURES
Table 2.1 Nitration with molar equivalents of nitrating agent
Table 2.2 Nitration with excess nitrating agent
17
21
Figure 2.1 Aromatic Region of the 300MHz 1 H-NMR Spectrum of
1-chloro-4-nitrobenzene 23b in d6-acetone
19
Figure 2.2 Aromatic Region of the 300MHz 1 H-NMR Spectrum of
2,4-dinitroanisole 24e in d6 -acetone
25
VI
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LIST OF SCHEMES
Scheme 1.1 Boroxine formation 2
Scheme 1.2 Suzuki cross-coupling reaction 3
Scheme 1.3 Multicomponent synthesis of a-arylglycines 3
Scheme 1.4 Synthetic routes to arylboronic acids 5
Scheme 1.5 Nitration of 1,4-bis(isopropyl)benzene 7
Scheme 1.6 /psosubstitution of arylsilanes 8
Scheme 1.7 Ipso-substitution of arylboronic acids with N-
halosuccinimides 9
Scheme 1.8 Formation of trifluoroacetyl nitrate 9
Scheme 1.9 Nitrations of phenylboronic acid 10
Scheme 2.1 Regioselective nitration of arylboronic acids 15
Scheme 2.2 Structures and estimated chemical shifts for dinitroanisole
isomers 23e and 23y 24
Scheme 2.3 Complexation of arylboronic acids 27
Scheme 2.4 Pathway to dinitration 28
Scheme 2.5 Proposed mechanistic pathway for the reaction 30
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ABSTRACT
Electrophilic nitrations of phenylboronic acids with ammonium nitrate and
trifluoroacetic anhydride were investigated at low temperatures. The reactions give
the /pso-nitrated compounds, the desired regioselectivity, in good yields.
Competing nitration of the phenylboronic acids at other ring positions was
also observed. Dinitro compounds of activated and deactivated aromatic ring
systems were obtained at -45°C in moderate to good yields.
A mechanistic pathway for the nitration is proposed and the effects of the
amount of nitrating agent employed on the product composition is shown.
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1 General Introduction
Although arylboronic acids1 have been available for more than one hundred
years, they have not been used much in organic synthesis until recently. Since
they are comparatively stable organometallic compounds they have a wide range
of applications in organic synthesis.
1.1 Properties and Applications of Arylboronic Acids
Phenylboronic acid was first prepared in 1880 by Michaelis and Becker.2 It
was expected to have mild antiseptic activity, like boric acid. In the 1930s, it was
shown that various arylboronic acids are toxic towards microorganisms while being
relatively harmless towards higher animals.3
Almost all arylboronic acids are high-melting, crystalline compounds that
are convenient to handle, due to their relatively low toxicity and stability to air and
water. They can be characterized quite easily by NMR-spectroscopy, especially
their 1 1 B-NMR spectrum distinguishes them from other boron-containing
compounds.
Formation of cyclic trimeric anhydrides (boroxines) is characteristic for
arylboronic acids (Scheme 1.1). This dehydration equilibrium means that traces of
anhydride are always present in the boronic acids.4 Since their reactivity is very
similar, this does not seem to be a problem for the reactions covered in this thesis,
1
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but the calculation of yields is subject to some uncertainty because of the different
molecular weights.
Ar
/
Ar— B(OH) 2
+ 3 H20
- 3 H20
Scheme 1.1 Boroxine formation
Phenylboronic acid has been used to protect diols and in stereocontrolled
Diels-Alder reactions.56 Recently, arylboronic acids have attracted increasing
attention for their novel molecular recognition properties.7 The probably most
widely used application of arylboronic acids in organic synthesis is the Suzuki
cross-coupling reaction.8 This palladium(0)-catalyzed reaction provides a
convenient way to form carbon-carbon bonds under very mild conditions. It is
mostly used to form asymmetric biaryls from aryl halides (Scheme 1.2), but alkenyl
halides and triflates can also be employed.
2
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Ar’— X
3
Ar— B(OH) 2
1
Pd (0) and base
Ar—Ar’
4
X = Br, I
Scheme 1.2 Suzuki cross-coupling reaction
Petasis and Zavialov have reported an efficient one-step, three-component
synthesis of p.y-unsaturated a-amino acids from alkenylboronic acids, amines and
a-ketoacids.9 They have also reported a conceptually related Boronic Acid
Mannich reaction between an arylboronic acid, an amine and an a-keto acid
(Scheme 1.3).1 0 This new one-step three-component approach yields a-
arylglycines in very good yields. The reaction is practical and experimentally
convenient, often proceeding by simple stirring of the three components at room
temperature over several hours. If certain chiral amine auxiliaries are used,
optically active arylglycine derivatives in up to 99% de can be obtained.
R
OH
CH2Cl2 or toluene
RT
5 6 7 OH
Scheme 1.3 Multicomponent synthesis of a-arylglycines
3
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Arylboronic acids are increasingly used in the industrial production of
pharmaceuticals or novel organic materials.1 1 Convenience in handling and their
availability makes them especially attractive to large-scale synthesis. In the last
two years, a growing number of them has become available from traditional
vendors such as Aldrich,1 2 but smaller vendors specializing in this field1 3 are
constantly increasing their inventory.
1.2 Preparation of Arylboronic Acids
The first preparation of phenylboronic acid was carried out by hydrolysis of
phenylborondichloride obtained from the reaction of diphenylmercury and boron
trichloride.2 For most synthetic purposes, there are several facile routes to
arylboronic acids (Scheme 1.4).1 4 ,1 5
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(Ar)3B
> A / '
8
+ Ar—X
1. PdCI2 (dppf)
KOAc/ DMSO
2. H3 CT
Ar—B(OH)2
1. Mg / Et20 or
BuLi / Et20
2. BY3
3. H3 Cf
Ar—X
3
10
Scheme 1.4 Synthetic routes to arylboronic acids
Reaction of trialkylborates with arylmagnesium or aryllithium reagents has
become the most important source for arylboronic acids. Aryllithium compounds
can easily be prepared either by halogen-metal exchange from aryl halides 3 and
n-butyllithium or by direct metallation of substituted aromatics with f-butyllithium.1 6
The palladium-catalyzed coupling between aryl halides 3 and alkoxydiboron
derivatives 9 is another convenient way.1 7
5
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1.3 Electrophilic /pso-Substitution of Arylboronic Acids
1.3.1 Background: /pso-Substitution Reactions
Aromatic substitution reactions have been investigated extensively.
Directing effects of various substituents and the classification of activated and
deactivated aromatic compounds are well known. To describe different positions
relative to a substituent on aromatic systems, ortho, meta and para are generally
used. When an electrophile attacks a substituted aromatic ring directly at the
position bearing the substituent, the attack is at the /pso-position.1 8 A substituent
gets replaced the easier, the better it can stabilize a positive charge. This
characteristic also decides whether the attacking electrophile or the existing
substituent is separated off in the rearomatisation of the a-complex.
Applications of ipso-substitution reactions are rather rare, therefore it seems
appropriate to describe the most-common ones. The ipso-dealkylation is relatively
common. Since the alkyl group is separated off as a carbocation, the process is
favored for branched alkyl groups. The nitration of 1,4-bis(isopropyl)benzene is a
good example (Scheme 1.5).1 9
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A
CH(CH3 ) 2 CH(CH3 ) 2 CH(CH3)2
HNO.
no 2
+
h 2 so.
CH(CH3 ) 2 CH(CH3 ) 2
12
n o 2
11
13
Scheme 1.5 Nitration of 1 ,4-bis(isopropyl)benzene
Desulfonation, decarboxylation and dehydroxylation have also been
investigated.1 8 2 0 The most intensively studied group of /psosubstitutions is the
electrophilic substitution of arylsilanes 14 (Scheme 1.6).2 1 Due to the polarization
of the carbon-siiicon bond, the ipso position is “ electron rich”. In addition to that,
silyl substituents stabilize structures with carbenium-character at the p-carbon
(Scheme 1.6: 15a and 15b). Since these reactions are very fast, they are
especially versatile for applications that require m ild conditions.2 2
7
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SiRa
14
£
E SiR3
X
E SiR3
E SiR
X
©
I
I I
15a
15b 15c
16
Scheme 1.6 /pso-substitution of arylsilanes
1.3.2 /pso-Substitution of Arylboronic Acids
Several applications of /pso-substitution of arylboronic acids have been
reported. Aryl azides can be prepared indirectly from arylboronic acids by in situ
conversion into aryl-lead triazetates and reaction with sodium azide.2 3 The
preparation of fluoroarenes by reaction with caesium fluoroxysulphate is not a
direct substitution either2 4
In a continued effort to investigate the electrophilic reactivity of arylboronic
acids and aryltrifluoroborates our research group has demonstrated the ipso
bromination and ipsoiodination with N-halosuccinimides 17 (Scheme 1.7).2 5
8
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Ar— B(OH) 2
1
MeCN
Ar—X
9
X = Br.l
Scheme 1.7 /pso-substitution of arylboronic acids with N-
halosuccinimides
1.4 Electrophilic Nitration
There is extensive data available for the nitration of arenes.2 6 This has lead
to a very good understanding of the steps involved in the nitration reaction 2 7
Several reagents are available, the most common ones are mixtures of nitric and
sulfuric acid, nitronium tetrafluoroborate2 8 and acetyl nitrate. Crivello introduced
mixtures of ammonium nitrate 19 and trifluoroacetic anhydride 18 to nitrate a
variety of aromatic compounds at room temperature in good yield.2 9 Trifluoroacetyl
nitrate3 0 20 seems to be the reactive nitrating agent in analogy to acetyl nitrate
(Scheme 1.8).
O O
CF3COCCF3 + NH4NO3
18 19
O
CF3CONO2
20a
O
CF3CO' no2+
20b
Scheme 1.8 Formation of trifluoroacetyl nitrate
9
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Ainley and Challenger first carried out nitration of phenylboronic acid in
1930.3 1 Harvey and Norman reinvestigated their results and found that depending
on the reagent used, the product mixture can be shifted towards either the meta or
the ortho product (Scheme 1.9).3 2 In all cases what appears to be the ipso-
substituted product, nitrobenzene, was also obtained. However, as discussed
later, this does not imply only /pso-substitution.
B(OH) 2
1a
HN0 3 + H2 S 0 4
-20° C
B(OH) 2
'NO?
21
70%
B(OH) 2
HNO3 + Ac-,0
-15° C
1a
B(OH) 2
-NO,
22
60%
Scheme 1.9 Nitrations of phenylboronic acid
Other studies include the nitration of phenylboron dichloride, which
proceeds very slowly with overall yields of 10-20% with ortho/meta/para product
composition.3 3
10
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Nitroarenes are desirable, since they play important roles as precursors to
industrially or synthetically interesting compounds. Especially the reduction to
amines is valuable. Diazotation and Sandmeyer-type reactions can yield a variety
of other compounds.
1.5 Thesis Scope
After 150 years, the study of nitration remains a vibrant
and significant field of chemistry. [...] It is thus with
confidence that we predict in the years to come an
even brighter and more exciting future for nitration
chemistry. At the same time we hope that when the
future investigators of the field look back to the efforts
of our generation they will feel that we did our best to
extent the knowledge of nitration, one of the most
fundamental reactions in chemistry. (Olah et a/.,
1 989)2 7 ( c >
Although the nitration of arenes is one of the most widely studied
electrophilic aromatic reactions, there are still challenges that remain. Most of the
reactions proceed with isomeric product distributions. One of the goals of our
investigation was to try to obtain the ipso-substituted products with desired
regioselectivity. Most nitration reagents are also strong oxidizers. If milder reaction
conditions can be applied, the reaction becomes more versatile to a wider range of
substrates. Especially in natural product or target molecule synthesis, chemists
need other reactions to introduce the biologically important nitro-functionality, or
use it as a precursor to a variety of other compounds. Furthermore, the
11
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withdrawing effect of the nitro group often prevents poiynitration. Since highly
energetic materials often contain nitro groups, it might be desirable to develop
methods to add multiple nitro groups under milder conditions.
Having investigated the reactivity of arylboronic acids towards several
electrophiles, the nitration still remained a challenge to us. Earlier attempts and
reagent screenings have given some insight into the field. This thesis describes a
successful way to prepare the mono- and dinitrated compounds in moderate to
good yields. In addition to that, the proposed pathway of the reaction might give
some ideas for the proposed nucleophile assisted electrophilic substitution, a
mechanism that remains to be investigated in detail.
12
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1.6 References
1 Negishi, E. Compreh. Organomet. Chem. 1983, 7, 323.
2 Michaelis, A.; Becker, P. Ber. 1880, 13, 58.
3 Seaman, W.; Johnson, J. R. J. Am. Chem. Soc. 1931, 53, 711.
4 Michaelis, A.; Becker, P. Ber. 1882, 15,182.
5 Suguhara, J. M.; Bowman, C. M. J. Am. Chem. Soc. 1958, 80. 2443.
6 Narasaka, K; Shimada, S.; Osoda, K.; Iwasawa, N. Synthesis 1991,1171.
7 Suenaga, H.; Yamamoto, H.; Shinkai, S. PureAppl. Chem. 1996, 68, 2179.
8 Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
9 a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. b) Zavialov, I.
A. Dissertation, University of Southern California: Los Angeles, 1998,154.
1 0 Zavialov, I. A. Dissertation, University of Southern California: Los Angeles, 1998,
205.
1 1 Tour, J. M. Chem. Rev. 1996, 96, 537.
1 2 Aldrich Chemical Co., Inc., Milwaukee, Wl.
1 3 Frontier Scientific, Inc., Logan, UT.
1 4 Koster, R. in Methoden der organischen Chemie (Houben-Weyl), 4th ed., Vol.
13/3a, Koster, R., ed.; Thieme: Stuttgart, 1982, 617.
1 5 Matteson, D. S. in Chemistry of the Metal Carbon Bond, Vol. 4, Hartley, F. R.,
ed.; Wiley: Chichester, 1987, 307.
1 6 Snieckus, V. Chem. Rev. 1990, 90, 879.
1 7 Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.
1 8 (a) Perrin, C. L. J. Org. Chem. 1971, 36, 420; (b) Perrin, C. L.; Skinner, G. A. J.
Am. Chem. Soc. 1971, 93, 3389.
1 9 Olah, G. A.; Kuhn, S. J. J. Am. Chem. Soc. 1964, 86, 1067.
13
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2 0 (a) Traynham, J. G. J. Chem. Education 1983, 60, 937; (c) Fischer, A.;
Henderson, G. N.; RayMahasai, S. Can. J. Chem. 1987, 65, 1233.
2 1 (a) Deans, F. B.; Eabom, C. J. Chem. Soc. 1959, 2299; (b) Eabom, C.; Bott, R.
W. in Organometallic Compounds of the Group IV Elements, Vol. 1, Part 1,
MacDiarmid, A. G., ed.; Marcel Dekker, Inc.: New York, 1968, 407.
2 2 Wilson, S. R.; Jacob, L. A. J. Org. Chem. 1986, 51,4833.
2 3 Huber, M.; Pinhey, J. T.; J. Chem. Soc. Perkin Trans. 1 1990, 721.
2 4 Clough, J. M.; Diorazio, L. J.; Widdowson, D. A. Synlett 1990, 761.
2 5 (a) Thiebes, C.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett 1998,141 ;
(b) Thiebes, C. Thesis, University of Southern California: Los Angeles, 1997.
2 6 Stock, L. M. Prog. Phys. Org. Chem. 1976, 12, 21.
2 7 (a) Olah, G. A.; Kuhn, S. J. in Friedel-Crafts and Related Reactions, Vol. 2,
Olah, G. A., ed.; Wiley-lnterscience: New York, 1964, 1393; (b) Olah, G. A.
American Chemical Society Symposium Series, Vol. 22, Albright, F. A., ed.;
Washington, D. C., 1976, 1 (c) Olah, G. A.; Malhorta, R.; Narang, S. C. Nitration
- Methods and Mechanism-, VCH: New York, 1989; (d) Schofield, K. Aromatic
Nitration; University Press: Cambridge, 1980.
2 8 (a) Kuhn, S. J.; Olah, G. A. J. Am. Chem. Soc. 1961, 83, 4564; (b) Olah, G. A.;
Kuhn, S. J. J. Am. Chem. Soc. 1962, 84, 3684; (c) Olah, G. A.; Prakash, G. K.
S.; Wang Q.; Li, X. In Encyclopedia of Reagents for Organic Synthesis, Vol. 6,
Paquette, L. A., ed.; Wiley: Chichester, 1995.
2 9 Crivello, J. V. J. Org. Chem. 1981, 46, 3056.
3 0 Even, C.; Fauquenoit, C.; Claes, P. Bull. Soc. Chim. Belg. 1980, 89, 559.
3 1 Ainley, A. D.; Challenger, F. J. Chem. Soc. 1930, 2171.
3 2 Harvey, D. R.; Norman, R. O. C. J. Chem. Soc. 1962, 3823.
3 3 Olah, G. A.; Piteau, M.; Laali, K.; Rao, C. B.; Farooq, O. J. Org. Chem. 1990, 55,
46.
14
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2 Results and Discussion
2.1 Regioselective /pso-Nitration
The regioselective nitration of arylboronic acids with ammonium nitrate and
trifluoroacetic anhydride was successfully carried out. In all cases, the ipso-
substituted product was obtained.
B(OH) 2
NO,
NH4 N 0 3 + (CF3 C0)20
19 18
c h 3cn
-45° C
23
Scheme 2.1 Regioselective nitration of arylboronic acids
In order for the reactions to give acceptable yields, the procedure given by
Crivello1 had to be modified. The temperature had to be lowered to few degrees
above the freezing point of the solvent. In order to get good conversion, the
arylboronic acids were dissolved in acetonitrile and trifluoroacetic anhydride was
added prior to the addition of the nitrating agent. After a few seconds, a
suspension was obtained. Apparently, the trifluoroacetic esters were formed with
the boronic acid function and further complexation of the boron atom with
nucleophiles to the “ ate” like complex caused this precipitation. The suspension
15
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was then cooled to low temperature. The nitrating agent was prepared in a
separate flask, cooled to low temperature (-45°C) and slowly injected into the
reaction mixture.
Table 2.1 shows the results of the nitration using equimolar ratios of
arylboronic acids and ammonium nitrate. In all cases, the major product was the
/pso-substituted nitro compound. After column chromatography, the nitro-products
could be isolated in very good purity and were characterized by GCMS and NMR.
GCMS-analysis of the reaction mixtures indicated, that small amounts of
other isomers were present. This could only be explained in one of two ways:
a) ipso substitution takes place along with some formation of O-nitrosation
products (Ar-ONO).
b) initial substitution at other ring positions followed by protiodeboronation.
Direct evidence for a) could not be found. Especially in the case of 3-
methoxyphenylboronic acid 1g, appearance of 4-nitroanisole 23e gives substantial
evidence for b). There were only minimal amounts of the other isomers present
(usually less than 1 % from GC). TLC analysis did not indicate any isomers being
present. The two products from the reaction of 4-methoxyphenylboronic acid 1e
could be isolated and characterized.
16
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Table 2.1 Nitration with molar equivalents of nitrating agent
Substrate Produces) Yield [% 1
1a
.NOo
23a
78
C l
B(OH)2
1b
.NO,
c r
23b
65
.NO-
58
1c 23c
.B(OH)j
Br'
id
.N O ,
Br'
23d
57
^ V /B(OHfe
M i
le
.NO,
MeO"
0,N.
MeO
23e
.NO,
24e
63
12
continued on next page
17
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Table 2.1 (continued) Nitration with molar equivalents of nitrating agent
Substrate Produces) Yield [% 1
1 f
52
M e O ^
ig
MeO
MeO.
23e
MeOv
NO,
iS >
n o3
24x
49
15
<5
(by GCMS)
The likely pathways for this reaction are given later in this thesis and will
help explain the results obtained. In order to confirm the substitution patterns of the
isolated compounds, NMR analysis was used. Figure 2.1 shows the aromatic
region of the obtained 1H-NMR spectrum of the product from the reaction of 4-
chlorophenylboronic acid 1 b and the nitrating agent.
18
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a . 2 a . i a . i 7.9 7. a 7.7 ?.« pp«
Figure 2.1 Aromatic Region of the 300 MHz 'H-NMR Spectrum
of 1-chloro-4-nitrobenzene 23b in d6-acetone
The product is assigned as 1-chloro-4-nitrobenzene 23b. The spectrum
shows the characteristic 1,4-substitution pattern of the benzene ring: two doublets.
The coupling constant for this 3 Jh,h coupling is 9.0 Hz. This is in excellent
agreement to data found in the literature and matches the published spectrum for
the particular compound. Upon closer inspection of the spectrum, long-range
coupling with a coupling constant of about 2 Hz can be seen. This can be assigned
to the 4 Jh.h coupling.
Similar results were obtained from the NMR analysis of the other products
listed in Table 2.1. In all cases the spectrum could be assigned to the product of
the /ipso-substitution without doubt.
19
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2.2 Nitration with Excess Nitrating Agent: Formation of Dinitro Compounds
In order to see effects on composition and yield of products and to
investigate further details of the reaction, excess nitrating agent was used. The
appearance of unexpected isomers and the effects on decomposition of the
starting materials seemed particularly interesting.
In a first reaction, 4-chlorophenylboronic acid 1b was reacted with 4 molar
equivalents of the nitrating agent. TLC analysis showed existence of two different
compounds with significantly different polarity. Two separate peaks were obtained
in the GCMS analysis. The MS spectrum for the first GC peak showed the
expected mass and chlorine-atom isotope distribution for the mononitrated
product. The MS spectrum for the second peak showed the same chlorine-atom
isotope-distribution, but the mass showed an increase of 45 units compared to the
mononitrated species, a clear indication for the dinitrated product. Separation of
the products by column chromatography and subsequent NMR-analysis showed
that dinitro compounds were indeed obtained.
The results of the reaction with excess nitrating agent are summarized in
Table 2.2. The amount of nitrating agent used and the products obtained are
indicated.
20
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Table 2.2 Nitration with excess nitrating agent
Substrate Product(s)
Equivalents Yield
“N O /”
B(OH)2
2.5
5
2.5
5
15
8
45
47
2.5 45
5 32
2.5 25
5 46
8(OH)2
24c
continued on next page
21
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Table 2.2 (continued) Nitration with excess nitrating agent
Equivalents Yield
Substrate Product(s)
B(OH)2
continued on next page
22
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Table 22 (continued) Nitration with excess nitrating agent
Substrate Product(s)
Equivalents Yield
“NO;*" [%]
,NO,
3.0 35
HiC
0,N
23 i
1i
3.0 20
23
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The results show the influence of the nitrating agent on the product
composition. In most cases increase in the amount of nitrating agent results in the
increase in yield of dinitrated compound. In section 2.3 this data is being used to
develop a plausible mechanistic pathway for the reaction.
To confirm the configuration of the products, NMR-analysis was used. The
1H-NMR signals of the aromatic protons give clear evidence for the substitution
patterns. Figure 2.2 shows the aromatic region of the 1H-NMR spectrum of the
dinitrated product obtained from 4-methoxyphenylboronic acid 1e.
The obtained dinitro compound could be one of the two isomers 24e or 24y.
To distinguish the structures, a chemical shift increment system is used to predict
the chemical shifts for the protons in both structures.2 This increment system
quantitatively estimates electronic effects of the substituents in ortho/ metal para
position to the particular hydrogen.3 The obtained values are listed in Scheme 2.2.
OMe
NO-
8 7.3
88.5
89.0
N0 2
OMe
8 7.4 8.0
NO;
88.4
N0 2
24e
24y
Scheme 2.2 Structures and estimated chemical shifts for
dinitroanisole isomers 23e and 23y
2 4
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Figure 2.2 Aromatic Region of the 300 MHz 1H-NMR spectrum
of 2,4-dinitroanisole 24e in d6-acetone
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The structures can be distinguished by looking at the signal for H6. That
hydrogen can clearly be assigned to the most shielded aromatic signal obtained
for both 24e and 24y, corresponding to the doublet at 8 7.6 in Figure 2.2. The
coupling constant of 9.0 Hz indicates a 3 J coupling. That is clear evidence for 24e.
Molecule 24y would require the most shielded signal to show the 4 J coupling to H2
as well, there should be a doublet of doublets for the most shielded aromatic
signal. In 24e there is no hydrogen present to show any 4Jh,h coupling for that
signal. Therefore structure 24e is assigned to the spectrum in Figure 2.2. H3 gives
the most deshielded signal at 8 8.7, a doublet with 4 Jh,h=2.7Hz (coupling to H5). At
around 8 8.5 the doublet of doublets is assigned to H5. The splitting is due to
3 j h h=9.3 Hz to H6 and 4 Jh,h=2.7Hz to H3. The doublet at 8 7.6 is assigned to H6
and shows 3 Jh,h=9.2Hz to H5. The data is in good agreement with the published
data for 3 Jh,h and 4 Jh.h coupling constants on aromatic systems. 4
2.3 Proposed Mechanistic Pathway
Based on the experimental data, a pathway for the reaction is being
proposed in this section. In order for most of the substrates to react, trifluoroacetic
anhydride had to be added to the arylboronic acids prior to addition of the nitrating
agent. Precipitation of an “ ate” like complex was observed initially and the
suspension was subsequently treated with the nitrating agent. This step was
crucial to get good conversion and essential in the case of deactivated aromatics.
This first step of the reaction can probably be described as shown in Scheme 2.3.
26
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8 - ^
•OR
B(OH)2
Nu— B J------ D-— -
OR
(CF3 C0)20
18
c h 3c n
X
25
R=H, C(0)CF 3
Nu=(CF3 C0)2 0, CF3 COOH. c h 3cn
Scheme 2.3 Complexation of arylboronic acids
Since there are different “nucleophiles" present in the reaction mixture it is
unclear which Nu (if at all) complexes to the boron in intermediate 25 (an “ ate” like
complex). Furthermore, the structure is probably temperature dependent and will
vary from room temperature to the reaction temperature at -45°C. The nucleophilic
attack on the boron makes the ipso-position more electron rich resulting in
increasing reactivity of the ipso-position.
There are several potential ways to form the dinitro-product. One could
think of the /pso-substitution, followed by a second nitration of the mononitro
compounds. For most of the substrates used, this does not seem to be a
reasonable explanation. Crivello found that nitrobenzene does not react with the
reagent at room temperature. 1 In a control experiment, 1 -chloro-4-nitrobenzene
23b and nitrobenzene 23a were reacted with the reagent mixture in a freezer at
-25°C. After several days, no dinitro compounds could be detected by GCMS.
27
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Only very activated aromatics such as 4-nitroanisole 23e might further react to
form the dinitro compound from the mononitrated species.
We can therefore assume, that there is a competition between the ipso-
substitution and nitration on the other ring positions of the arylboronic acid. Based
on the substituents present, the substitution can occur at other positions. This
substitution can then be followed by the ipso-substitution of the boron functionality
to give the dinitro compounds (Scheme 2.4). Being able to form dinitroarenes at
low temperatures was not anticipated. It seems that the reactive intermediate 26
can very readily be nitrated at the /psoposition, even if nitro-groups are present
and deactivate the aromatic ring.
24
Scheme 2.4 Pathway to dinitration
28
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In order to explain the formation of isomeric mononitrates products (for
example 23k and 23c from 1k, Table 2.2), other reactions have to occur from
intermediate 26. It is assumed that protons cause electrophilic protiodeboronation.
This is another example of /pso-substitution, with a proton as the attacking
electrophile. Some of the reactions listed in Section 1 .4 also showed nitrobenzene
as byproduct. Whether this was caused by direct /pso-substitution of the boronic
acid functionality with the nitrating electrophile, or nitration on other ring positions
and ispo-substitution by protons is unclear. Both pathways would lead to the same
products. However, this reaction seems to be of minor importance for the
conditions listed in this thesis. The regioselectivity of the nitrations listed in Table
2 . 1 shows that the /pso-nitration is the predominant reaction and thus
nitrodeboronation takes place.
Summarization of the mechanistic pathway is given in Scheme 2.5. The
competition between nitration at the /pso-position and other ring-positions
determines the mononitro/dinitro ratio of the products in most cases. Unless for
highly activated aromatic systems, no further nitration is possible from 23. The
activated boron-functionality appears to be a good “ leaving group” so the ipso-
nitration can occur readily at low temperatures, even if another nitro-group
diminishes the nucleophilic nature of the aromatic ring system.
29
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X
25
Nu— B
" N 0 2 "
Scheme 2.5 Proposed mechanistic pathway for the reaction
The reaction could be described as a “ nucleophile assisted electrophilic
substitution”. A nucleophile enhances the polarity of the carbon-boron bond,
increasing the reactivity for electrophilic /pso-substitution. This terminology,
30
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however, has to be used with great caution. It seems unreasonable to have both
nucleophiles and electrophiles present at the same time without a reaction
between the two occurring. The nucleophiles present are mostly molecules with
electron-donating capabilities (Lewis bases), such as the oxygen-atoms in
trifluoroacetic-anhydride. The interaction between Nu and the boron in 25 is
probably better described as a (weak) coordination which causes the boron to get
partially anionic character (an “ ate” like complex). This complexation for boron is
known and has been reported for the related complex of phenylboronic acid and
acetic anhydride. 5
2.4 Conclusion and Outlook
The regioselective nitration of arylboronic acids under mild conditions has
been shown successfully. Despite the directing effects of other substitutents
present, the ipso-substitution is the major reaction. 3-Bromophenylboronic acid 1f
could be selectively nitrated to 1 -bromo-3-nitrobenzene 23f. For 3-
methoxyphenylboronic acid 1g, the ispo-nitrated product 3-nitroanisole 23g was
the major product with little 4-nitroanisole 23e. If excess nitrating agent is used,
dinitro-products are formed and can be isolated. The conversion proceeds with
moderate to good yields.
The reaction is probably not practical for the preparation of most of the
compounds investigated, since they are available more inexpensive commercially.
However, for regioselective introduction of nitro-groups, the reaction is very well
31
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suited. Due to the mild reaction conditions, the reaction could be interesting for a
broad range of compounds. Nitro-groups play important roles in biologically active
molecules and could be selectively introduced by this method.
To the best of our knowledge, conversion of halogen- to nitro-functionality
cannot be done easily. This method could achieve this task, by first converting the
halogen into a boronic acid (see table 1.7) and then an /pso-substitution to the nitro
compound.
It is also possible to introduce 1 5 N labeled nitro-groups with this procedure.
1 5 N enriched ammonium nitrate is available commercially6 and can be employed in
the preparation of the nitrating agent. This might be valuable for biological studies
and synthesis of target-molecules in pharmaceutical research.
The reaction was also briefly investigated on alkenylboronic acid systems.
First results show similar reactivity to the one described in this thesis. Synthesis of
geometrically pure nitroalkenes might be very useful and will be investigated in the
future.
A reasonable mechanistic pathway for this reaction was developed using
the results obtained and based on known reactivity on aromatic systems. Future
investigations could make use of labeling experiments to investigate the
regioselectivity and the different steps involved in this reaction.
32
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2.5 References
1 Crivello, J. V. J. Org. Chem. 1981, 46, 3056.
2 Hesse, M.; Meier, H.; Zeeh, B. Spektroskopische Methoden in der organischen
Chemie, 5m ed.; Thieme: Stuttgart, New York, 1995,123.
3 Calculation was performed using the formula 5=7.26+11. The relevant increments
are ( lo r th o . I m e ta i Ip a ra )- H ( 0 , 0 , 0 ), N 0 2 ( 0.95, 0.26, 0.38),
OCH3 (-0.48, -0.09, -0.44)
4 Gunther, H. N M R Spectroscopy, 2n d ed.; Wiley; New York, 1995.
5 (a) Harvey, D.R.; Norman, R. O. C. J. Chem. Soc. 1962, 3823; (b) Olah, G. A.;
Piteau, M.; Laali, K.; Rao, C. B.; Farooq, O. J. Org. Chem. 1990, 55, 46.
6 Aldrich Chemical Co., Inc., Milwaukee, Wl
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3 Experimental
3.1 General Aspects
All reactions were conducted using Schlenk-techniques. Reaction flasks
were connected to the Schlenk-line and an argon-balloon and equipped with a
rubber septum. The flasks were evacuated, heated and filled with argon. For
addition or removal of solvents or reactants, PVC or glass syringes equipped with
steel needles were used. Solids were added under continuous argon flow.
The reactions were cooled to low temperatures using mixtures of dry ice
and acetone. This meant that the reaction temperature fluctuated within
approximately ± 5°C. In some cases a cryostat was used to keep the reactions
within a closer temperature range. However since this did not seem to influence
the reactivity and the product yields, the more convenient dry ice/acetone mixtures
were used.
Most chemicals employed were commercially available reagent grade
chemicals. No further purification was needed. Arylboronic acids were obtained
from Aldrich Chemical Co. 1 or Frontier Scientific, Inc.2 Solvents were dried and
purified using general laboratory procedures3 as well as using a solvent purification
system from Anhydrous Engineering. 4 This system “ pushes” the solvent through
columns containing activated aluminum oxide. The purity of the solvents obtained
is remarkable and the dryness was verified using a Kari-Fischer titration apparatus.
34
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Reactions were monitored by gas chromatography/mass spectrometry
(GCMS) on a Hewlett-Packard 5890 series GC mass spectrometer and by thin
layer chromatography (TLC). For TLC Merck 60 FR2 5 4 silica coated glass plates
and Kodak Chromagramm 13181 sheets with fluorescent indicator were used.
Product purification and separation was done using column
chromatography. Aluminum oxide and EM Science grade 62 silica gel was used
with mixtures of hexanes/ether as eluent. Use of a Cyclograph™ 5 has proven to be
extremely useful when separating isomers or mononitro/dinitro products. Due to
the high polarity, the time necessary for separation could be reduced with this
machine. Some products were purified with a Buchi GKR-51 Kugelrohr.
Characterization was done by GCMS, NMR and melting point
measurements. The MS spectrums were matched to the Hewlett-Packard nbs54k-
library to compare fragmentation patterns. NMR spectrums were obtained using a
Varian Unity 300, a Varian VXR 200 and a Bruker AMX 250 NMR spectrometer
using CDCI3 or d6 -acetone as solvents. Melting points were measured on a Mel-
Temp II instrument and if available melting points of a mixture of the product and
an authentic sample were taken to verify the identity. All of the products obtained
have already been characterized, therefore the data obtained was compared to the
published information to confirm the authenticity of the compounds. 6
35
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3.2 Nitration Reactions
3.2.1 General Procedure with Equimolar Nitrating Agent:
A solution of 1 mmol arylboronic acid in dry acetonitrile (10 ml) was
prepared, protected from air using Schlenk-techniques. Approx. 0.7 ml of
trifluoroacetic anhydride was added through a septum and the mixture stirred at
room temperature for about 5 minutes. The mixture was cooled to -45°C using dry
ice/acetone mixtures and stirred for about 5 minutes. In a separate flask, an
equimolar amount of ammonium nitrate was reacted in little acetonitrile (about 3
ml) at 0 °C with the amount of trifluoroacetic anhydride necessary to dissolve all the
solid (Caution! Violent reaction, trifluoroacetic anhydride was added slowly). The
flask was cooled in the dry ice/acetone bath. The reagent was very slowly (within
10-15 minutes) injected under constant stirring using a syringe. After the given
reaction time, the cooling bath was removed and the reaction allowed to warm to
room temperature. The solvent was removed under reduced pressure and the
residue dissolved in ethyl acetate. This solution was passed through a short
column of silica gel with a small layer of aluminum oxide on top. The solvent was
removed and the residue purified on a silica gel column or on the Cyclopgraph™
with gradient hexane:diethyl ether mixtures from 100:1 to 1:1. The solvent was
removed and the products recristallized from pentane/ether and/or purified with a
Kugelrohr.
36
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3.2.2 General Procedure with Excess Nitrating Agent:
Similar to the previous procedure for equimolar nitrating agent with the
following exceptions: The given amount of ammonium nitrate was dissolved in 3-5
ml of acetonitrile and the amount of trifluoroacetic anhydride necessary. The
reagent was added faster (approx. within 3-5 minutes). Purification was more
complicated and sometimes required a second column chromatography
separation, especially for the dinitro-products.
3.3 Mononitro Compounds Prepared
23a Nitrobenzene
Procedure 3.2.1: Reaction time 4 hours, yield 78%.
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 678A.
NO
23b 1 -Chloro-4-nitrobenzene
Procedure 3.2.1: Reaction time 5 hours, yield 65%.
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 695A.
37
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23c 1 -Fluoro-4-nitrobenzene
Procedure 3.2.1: Reaction time 5 hours, yield 58%.
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 694C.
NO
23d 1 -Bromo-4-nitrobenzene
Procedure 3.2.1: Reaction time 5 hours, yield 57%.
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 695B.
NO;
MeO'
23e 4-Nitroanisole
Procedure 3.2.1: Reaction time 2 hours, yield 63%, byproduct isomer 24e
in 1 2 % yield.
1 H and hC NMR: Ref. 5, Vol. 2, 696A.
23f 1 -Bromo-3-nitrobenzene
Procedure 3.2.1: Reaction time 5 hours, yield 52%.
NMR: Lit. 7
38
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23g 3-Nitroanisole
Procedure 3.2.1: Reaction time 2 hours, yield 49%, byproduct isomer 23e
in 15%. Less than 5% dinitro compound detected by GCMS.
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 689C.
NO;
MeO'
23e 4-Nitroanisole
Procedure 3.2.1: Reaction time 2 hours, yield 63%, byproduct isomer 24e
in 1 2 % yield.
1 H and ’3 C NMR: Ref. 5, Vol. 2, 696A.
3.4 Dinitro Compounds Prepared
0 2N N O j
24a 1,3-Dinitrobenzene
Procedure 3.2.2: Reaction time 6 hours.
- 2.5 molar equiv. of NH4NO3: yield 45% (15% of 23a)
- 5.0 molar equiv. of NH4NO3: yield 47% (8% of 23a)
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 692A.
39
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24b 1 -Chloro-2,4-dinitrobenzene
Procedure 3.2.2: Reaction time 6 hours.
- 2.5 molar equiv. of NH4NO3: yield 25% (45% of 23b)
- 5.0 molar equiv. of NH4NO3: yield 46% (32% of 23b)
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 750A.
24c 2,4-Dinitrofluorobenzene
Procedure 3.2.2: Reaction time 5 hours.
- 3.5 molar equiv. of NH4NO3: yield 30% (30% of 23c)
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 749C.
NO;
24d 1 -Bromo-2,4-dinitrobenzene
Procedure 3.2.2: Reaction time 6 hours.
- 3.5 molar equiv. of NH4NO3: yield 42% (37% of 23d)
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 692A.
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24e 2,4-Dinitroanisole
Procedure 3.2.2: Reaction time 3 hours.
- 2.5 molar equiv. of NH4NO3: yield 49% (1 0 % of 23e)
- 5.0 molar equiv. of NH4 NO3 : yield 6 8 % (<5% of 23e)
NMR: Lit.8
NO; o2 n
EtO-
24h 1 -Ethoxy-2,4-Dinitrobenzene
Procedure 3.2.2: Reaction time 3 hours.
- 2.5 molar equiv. of NH4 N03: yield 35% (<3% of 23h), very messy reaction
NMR: Lit. 7
NO;
H3C'
24i 2,4-Dinitrotoluene
Procedure 3.2.2: Reaction time 4 hours.
- 3.0 molar equiv. of NH4NO3: yield 2 0 % (35% of 23i)
1 H and 1 3 C NMR: Ref. 5, Vol. 2, 749A.
41
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3.5 References
1 Aldrich Chemical Co., Inc., Milwaukee, Wl.
2 Frontier Scientific, Inc., Logan, UT.
3 Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, Vol. 3;
Pergamon:Oxford, 1988.
4 Anhydrous Engeneering, Granada Hills, CA.
5 Cyclograph™, Analtech, Inc., Newark, DE.
6 Pouchert, C. J.; Behnke, J. The Aldrich Library of 1 3 C and 1 H FT NMR Spectra,
Edition I, Vol. 1-3; Aldrich Chemical Co., Inc.: Milwaukee, 1993.
7 Shapiro, B. L.; Mohrmann, L. E. J. Phys. Chem. Ref. Data 1977, 6, 919.
8 Stephens, M. D.; Reinheimer, J. D.; Kappelman, A. H. Can. J. Chem. 1971, 49,
3759.
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Asset Metadata

Creator Salzbrunn, Stefan (author)

Core Title Nitration of arylboronic acids

School Graduate School

Degree Master of Science

Degree Program Chemistry

Degree Conferral Date 1999-08

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag chemistry, organic,OAI-PMH Harvest

Language English

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