Regiospecific P-Bromination of Activated Aromatic Systems

76 Pages·2017·1.75 MB·English

Western Kentucky University
TopSCHOLAR®
Masters Theses & Specialist Projects Graduate School
Spring 2017
Regiospecific P-Bromination of Activated Aromatic
Systems – Greener Approach
Elnaz Jalali
Western Kentucky University, [email protected]
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Projects.Paper 1950.
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REGIOSPECIFIC P-BROMINATION OF ACTIVATED AROMATIC SYSTEMS –
GREENER APPROACH

A Thesis
Presented to
The Faculty of the Department of Chemistry
Western Kentucky University
Bowling Green, Kentucky

In Partial Fulfillment
Of the Requirements for the Degree
Master of Science

By
Elnaz Jalali
May 2017
REGIOSPECIFIC P-BROMINATION OF ACTIVATED AROMATIC SYSTEMS-
GREENER APPROACH
Date Recommended
Dr. D. W. Slocum, Thesis Chair
Dr. Rui Zhang
Dr. Kevin Williams
Dean, Graduate School Date
I dedicate this thesis to my parents, Nasrin Bayati and Farzan Jalali, who
have been great inspirations to me and who have always been there for me. I am
forever grateful for such endless support and reassurance. I also dedicate this
work to Dr. Donald Slocum who helped greatly in editing this manuscript and in
directing this project.

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ACKNOWLEDGEMENTS
I would genuinely like to thank every person that has been a part of my life
during my years at Western Kentucky University. Many thanks are given to Dr.
D.W. Slocum for his support and encouragement throughout my entire graduate
program as a research assistant. I also want to acknowledge my Friends, Abdullah
Raza, Ali Abdulrheem, Kyle Reinscheld, and Emily Maulden, for their support and
most importantly their friendship. During the entire process, I have grown as a
distinguished individual and become a proficient scientist.
I would like to thank the entire Western Kentucky University chemistry
professors and the chemistry department faculties especially Dr. Rui Zhang and
Dr. Kevin Williams for being on my graduate committee.
Lastly, I would like to thank my family; my parents and my lovely brother
for their love and support throughout my life. Without them, I would not have been
able to accomplish all that I have today.

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TABLE OF CONTENTS
I. INTRODUCTION ......................................................................................... 1
A. Electrophilic Aromatic Substitution Reaction ......................................... 1
1. Background ................................................................................... 1
2. Mechanistic Aspects ....................................................................... 3
B. Bromination of Aryl Halides .................................................................... 8
1. Literature Review ............................................................................ 9
2. para-selective Bromination ............................................................. 10
II. PARA-BROMINATION OF VARIOUS SUBSTRATES ................................. 16
A. General Utilized Procedures ................................................................. 16
1. General Setup ................................................................................ 16
2. Preparation of the Samples ............................................................ 17
3. Isolation of the p-Brominated Products .......................................... 18
4. Instrumentation .............................................................................. 18
B. Experimental ......................................................................................... 19
1. General Procedure for p-Bromination of Aniline Aryls .................... 19
1.1) p-Bromination of Aniline ....................................................... 20
1.2) p-Bromination of Acetanilide ................................................. 20
2. General Procedure for p-Bromination of Phenol Aryls ................... 21
2.1) p-Bromination of 2-Methoxyphenol ....................................... 21
3. General Procedure for p-Bromination of Anisole Aryls ................. 22
3.1) p-Bromination of Anisole ...................................................... 22
3.2) p-Bromination of 1,2-Dimethoxybenzene ............................. 23
3.3) p-Bromination of 1,3-Dimethoxybenzene ............................. 24
3.4) p-Bromination of 1,4-Dimethoxybenzene ............................ 25
3.5) p-Bromination of 1,2,3-Trimethoxybenzene .......................... 25
3.6) p-Bromination of 1,2,4-Trimethoxybenzene .......................... 26
3.7) p-Bromination of 1,3,5-Trimethoxybenzene .......................... 27
4. General Procedure for p-Bromination of Naphthalene Aryls .......... 27
4.1) p-Bromination of 1-Methoxynaphthalene .............................. 28
4.2) p-Bromination of 2-Methoxynaphthalene .............................. 29
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TABLE OF CONTENTS (continued)
5. General Procedure for p-Bromination of Heterocycle Aryls ........... 29
5.1) p-Bromination of 1,3-Benzodioxole ....................................... 30
III. RESULTS & DISCUSSION ........................................................................... 33
IV. CONCLUSION .............................................................................................. 44
V. BIBLIOGRAPHY ........................................................................................... 46
VI. APPENDIX .................................................................................................... 51

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LIST OF FIGURES

Figure 1 Name and Structure of Sulfa Drugs Synthesized by EAS ............... 1
Figure 2 Electrophilic Aromatic Substitution Reaction Using Br2 ................... 2
Figure 3 Forming the sigma complex in an EAS reaction ............................. 3
Figure 4 Showing a Resonance Electron Donating Effect ............................ 4
Figure 5 Showing a Resonance Electron Withdrawing Effect ...................... 5
Figure 6 Dipole Moment for Substituted Benzene Ring ............................... 5
Figure 7 The Electrophilic Reaction of di-Substituted Aromatic Systems ...... 6
Figure 8 Tri-substituted Molecules Forming from di-substituted Molecules ... 7
Figure 9 The Resonance Structure of Stable Succinimide Anion ................ 12
Figure 10 Regiospecific p-Iodination Reaction .............................................. 14
Figure 11 Experimental Reaction in NBS/CH CN System ............................ 15
3
Figure 12 % GC yield vs. Equiv. of NBS (2-Methoxyphenol)......................... 39
Figure 13 % GC yield vs. Equiv. of NBS (1,4-Dimethoxybenzene) .............. 40
Figure 14 The Proposed Reaction Mechanism ............................................. 42

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LIST OF TABLES

Table 1 Reported Yields of p-brominated Aryl Derivatives ......................... 16
Table 2 Characterization Table of p-brominated Aryl Derivatives .............. 30
Table 3 Comparison of Yield/Time of p-Bromination in Different Media ..... 33

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REGIOSPECIFIC P-BROMINATION OF ACTIVATED AROMATIC SYSTEMS –
GREENER APPROACH

Elnaz Jalali May 2017 65 Pages
Directed by: Dr. D.W. Slocum, Dr. Rui Zhang, and Dr. Kevin Williams
Department of Chemistry Western Kentucky University
The halogenated derivatives of heterocyclic compounds (haloarenes) are
highly utilized in many fields of chemistry, including drug discovery, medicinal, and
material chemistry. There are a variety of ways to functionalize an aromatic system
and introduce halogen substituent into the ring. However, electrophilic aromatic
substitution (EAS) has been the focus of growing attention, particularly for electron-
rich substrates.
Electrophilic aromatic bromination protocols are one of the most important
electrophilic aromatic substitution reactions. However, preparation of bromoarenes
classically recommends the use of highly oxidative agents along with utilizing
various metal catalysts in a halogenated solvent. The corrosive and toxic nature of
these reagents and need of harsh conditions for these protocols make their utility
less desirable in current practice. Furthermore, lack of regioselectivity for most
substituted aromatics is the other distinguished drawback, since most products
contain ortho/para directors which afford a mixture of isomers.
The innovation of our procedure for the bromination of various substituted
aromatic compounds is twofold in that highly regiospecific para-bromination of
activated aryls by treatment with NBS has been accomplished. Although various
reaction mediums, such as cyclohexane, acetone, and acetonitrile has been used
in this procedure, the significant high yields of the product formation along with the
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