Regiospecific P-Bromination of Activated Aromatic Systems - Greener Approach
Regiospecific P-Bromination of Activated Aromatic Systems - Greener Approach
Regiospecific P-Bromination of Activated Aromatic Systems - Greener Approach
TopSCHOLAR®
Masters Theses & Specialist Projects Graduate School
Spring 2017
Recommended Citation
Jalali, Elnaz, "Regiospecific P-Bromination of Activated Aromatic Systems – Greener Approach" (2017). Masters Theses & Specialist
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
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
iii
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
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
professors and the chemistry department faculties especially Dr. Rui Zhang and
for their love and support throughout my life. Without them, I would not have been
iv
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
v
TABLE OF CONTENTS (continued)
vi
LIST OF FIGURES
vii
LIST OF TABLES
viii
REGIOSPECIFIC P-BROMINATION OF ACTIVATED AROMATIC SYSTEMS –
GREENER APPROACH
Directed by: Dr. D.W. Slocum, Dr. Rui Zhang, and Dr. Kevin Williams
highly utilized in many fields of chemistry, including drug discovery, medicinal, and
and introduce halogen substituent into the ring. However, electrophilic aromatic
substitution (EAS) has been the focus of growing attention, particularly for electron-
rich substrates.
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
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
ix
very short reaction times using acetonitrile make this approach more attractive.
That this regiospecific p-substitution takes place under such mild conditions leads
x
I. INTRODUCTION
A. Electrophilic Aromatic Substitution reaction
1. Background
and drug discovery. This impact has made scientists search for new
methodologies for the assembly of functional molecules. Although there are many
has been the extensively used method in many organic syntheses for the
as sulfa drugs. Sulfathiazole and Sulfadiazine were among the two most effective
sulfa drugs synthesized in the 1930’s by the method of EAS (Figure1). [1]
of over the counter drugs like ibuprofen, in which EAS is the first step where a
Friedel-Crafts acylation occurs. This method has been also utilized widely towards
procedure is highly utilized in many organic syntheses. However, there are some
Sulfathiazole Sulfadiazine
1
One downside of this substitution reaction is it does not afford regiospecific
Br2
FeBr3
Aside from this observation, frequently harsh conditions are necessary for
As a result, over the last decade, scientists are constantly seeking ways
eliminating the need to use hazardous and expensive oxidants with an overall
2
2. Mechanistic Aspects
Hughes) involves a two-step reaction. [3] The first step includes the attachment of
result, the π-bond will be replaced with two new sigma bonds, forming a
causing the ring to lose its aromaticity. [3] The second step proceeds rapidly by
releasing the hydrogen from the sigma complex to resume the stabilization
substituents, plays a vital role in governing the location where substitution will
occur and the overall rate of the electrophilic substitution reactions. [5]
Sigma Complex
Condensed Version
3
electron-rich substrates. This leads to consideration of the two different types of
groups such as –OH, –OMe, –Me, –NH2, –NHCH3, –NMe2, and –NHCOCH3, also
act as ortho/para directors. Therefore, the aromatic systems that bear activating
benzene ring by reducing the electron density on the ring through a resonance
–CHO, –CO2H –COCH3, –CO2CH3, and –CN, as EWGs direct the incoming
substituent to the meta- position. [6,7] However, halogens are also electron
:
_
:_ :
._.
The electron-donating group with a lone pair is able to stabilize the sigma
negative charge delocalizing the positive charge over several positions. When the
donating group has a delocalized unshared pair of electrons, the sigma complex
4
distributes the positive charge on the aromatic carbons showing the unshared
electron pairs in the ground state along with the 3 and 5 positions. As a result, the
charge in the ring. As a result, the electrophile primarily attacks the 3 and 5
Figure 6. Dipole displacements for electron withdrawing group on the left side
and electron donating group on the right side, producing meta-substitution and
meta-substitution ortho/para-substitution
5
Due to the fact that there are two ortho sites and only one para site, the
products than the para-substituted products (ratio of 2:1). Moreover, in the situation
where steric hindrance comes into effect, the incoming electrophile is more likely
to go to the position with the lower steric strain, resulting in the para position
polysubstituted benzenes, one must take account the individual effect of each
substituent. [9] In 2007, Forbes and his research group predicted a guideline to
systems. [10]
E or E+
6
Figure 8. Shown are various types of tri-substituted molecules forming
from di-substituted molecules. Dots and circles are symbols showing the locations
of the added substituent. A dot inside a circle (bull’s eyes) is a symbol showing the
highest probability of product outcomes, and the check marks illustrate the actual
which all possible trisubstituted patterns were created from di-substitution benzene
direct the coming third substituents to the actual location. Of the nine templates,
five of them were directed mainly by the properties of the deactivating and
7
activating preexisting groups on the ring. The remaining four templates with bull’s
eyes represent the cooperative directing effects in the placement of the third
substituent. [10]
applications. These small and structurally interesting aryl halides are particularly
metal mediated coupling reactions such as Stille, Suzuki, Heck, Sonogashira, and
Furthermore, contrary to iodine, bromine has a high affinity to react with most
organic compounds due to its higher electronegativity. [18] The activity and
utility of aromatic bromo compounds in the manufacture of numerous bulk and fine
8
achieved in such reactions by the careful selection of the reagents and synthetic
path. [19]
1. Literature Review
Although the procedures over past years have illustrated a vast variety of
paths to the para-selective bromination, the required harsh conditions are the main
For a while, the conventionally used approach to aryl bromides was the
bromination of arenes with liquid Br2 as a bromine source, which causes serious
suffers from the major drawback that has to be used in a high value because only
half of the bromine is utilized in the reaction and the other half generates
effectively reducing the atom efficiency by 50%. More importantly, this kind of
acidic waste products has a need of being neutralized before proceeding with
peroxide (H2O2), due to the fact that water would be the only by-product of these
reagents. However, poor regioselectivity and the explosiveness are the main
9
In some cases, alkali metal bromide salts including lithium bromide (LiBr),
potassium bromide (KBr), and sodium bromide (NaBr) have been used as the
alternative bromine source for the molecular bromine in the bromination process,
which are pretty safe compare to Br2. Nevertheless, due to low selectivity and low
methylene chloride have been widely utilized. However, various environmental and
health problems can be caused by the large-scale use of these solvents. Although
substrate materials, they are toxic and moreover all have a disadvantage of
as a mild Lewis acid catalyst, and acidic solids like chromatographic grade silica
[32] have been used. Most of these approaches require combination with highly
hazardous acids such as acetic acid [13], nitric acid [16], sulfuric acid [8,33] and
more importantly extensive time is needed for these reactions to obtain moderate
10
2. para-selective Bromination
In order to reduce health and safety risks, diminishing toxic waste, the cost
efficiency, and milder reaction condition the study of the combination of N-halo
succinimides (NXS) as a green halogenation agent with various medias has been
the focus of scientists for a long time. NXS as a great source of X+ can be used
products in high selectivity and good yields. [19,50] The structural features and
as a by-product. The major advantage of the use of NBS is producing the by-
product succinimide that is soluble in water and it can easily be washed and
11
Figure 9. The Resonance Structure of Stable Succinimide Anion [34]
Succinimide Anion
bromosuccinimide (NBS) became the most popular one due to the best yield of
oxidative reagents, various approaches have been envisioned for a wide variety of
substitution pathway has been proposed in numerous papers with the choice of
highly toxic nonpolar solvents like carbon tetrachloride (CCl4). However, the
environmental and health concerns resulted in the elimination of the use of CCl4 in
halogenation using NXS along with Cu-Mn spinel oxide as a catalyst. Though this
12
addition, this method has a disadvantage of using unnecessary reaction catalyst
along with the very long reaction of over 8 h for all utilized substrates. [48] A vast
arenes and heteroarenes with NBS revealed that all are either limited to specific
substrates or they do not provide a high yield of products with highest p-selectivity.
Moreover all stated disadvantages, some of these methods have a failing in that
the starting materials, as well as the solvents, must be used in large excess. A
number of acid-catalyzed NBS bromination strategies that are suffering from these
shortcomings and did not continue to be of interest are listed here including NBS-
substitution of Br+, which was generated from NBS, the only reagent is acetonitrile;
an accessible, affordable, and less hazardous polar solvent. All reactions were
carried out at room temperature, and generally high yield of the reaction was
13
when mild conditions were required (figure 10). With the use of hydrocarbon media
Media [4]
r.t
I2 HI (neutrilized)
Cyclohexane
aq. Na2CO3
would be a more interesting. Due to the fact that bromine is more electronegative
than iodine, it must show more affinity to react with a wide range of organic
great solvent medium. In spite of the yield of products for such reaction was high,
the strategy involved long reaction time. When the reactions were attempted with
cyclohexane, very low conversions were observed. We could not obtain a high
testified that the selectivity of the reaction is significantly dependent on the polarity
14
of the solvent medium and the para-selective brominations can be modified by
essential since the literature shows some polar solvents such as DMF poses
complications in solvent removal due to a high boiling point and water miscibility
[39].
found out acetone is pretty reactive toward NBS; however, acetonitrile does not
r.t.
NBS Succimide
Acetonitrile (20ml)
15
II. PARA-BROMINATION OF VARIOUS SUBSTRATES
1. General Setup
chemical company and used without purification unless otherwise indicated. All
magnetic stir bars were dried in a drying oven at 35°C to dry completely.
All reactions were run at room temperature (22°C). A clean, dry 50 mL round-
bottom one-neck flask was utilized to contain the reaction. First, a clean, dry
magnetic stir bar was placed into the 50 mL round-bottom one-neck flask. Next,
point, the flask was capped with a rubber septum and vented with a needle to the
open atmosphere. For some of the reactions, a slightly positive pressure of argon
(Ar) was inserted to the sealed reaction flask through a needle. Lastly, the dry
substrate was delivered slowly by the calculated volume to the stirring reaction in
different ways using a delivery needle through the septum of the reaction flask.
The reactions were allowed to stir for the specified time noted in Table 1.
16
Table 1. Reported Yields of p-brominated Aryl Derivatives
Purity of
Reaction GC Yield Isolated
Substrates Time (m) (%) products
Aniline 10 98.1 98.7
Acetanilide 15 91 100
Anisole 10 100 100
1,2-DMBa 60 95 98
1,3-DMB 20 94 100
1,4-DMB 5 86.5 100
1,2,3-TMBb 30 95 100
1,2,4-TMB 5 83 97.7
1,3,5-TMB 5 80.3 92.4
2-Methoxyphenol 60 67 88
1,3-Benzodioxole 90 93 98
1-Methoxynapthlene 5 100 100
2-Methoxynaphthalene 15 91 96.4
a. Dimethoxybenzene
b. Trimethoxybenzene
Around 1mL sample aliquots were taken from the reactions, using a glass
approximately 2mL of DI water to be quenched. The capped vial left to react with
the quench reagent for at least 20 min. After that, MTBE was added to the all
vortex mixer until the organic layer was clear. Approximately 1 μL aliquot of each
sample’s top layer was transferred directly from the 10 mL sample vial into the GC
vial for GC and GC/MS analysis. For NMR analysis, a small amount of crude
17
product was added to an NMR tube, followed by adding approximately 1 mL of
d.
For the isolation, the reaction mixture was transferred to the separatory
Each product migrates from the aqueous layer to the MTBE organic layer and was
then washed with DI water twice more. For the last wash, approximately 20 mL
brine was used before the organic layer was transferred into a 250 mL Erlenmeyer
flask. The product dried over sodium sulfate and then was transferred to the 100
mL round-bottom one-neck flask before going into the rotatory evaporator. Finally,
the crude brominated product, which is either solid or an oil was obtained after
solid products went through more purification were triturated with 10 mL of DI water
unless otherwise noted. Moreover, for NMR analysis, a small amount of pure
4. Instrumentation
conjugation with a BP-10 capillary column (25 m x 0.22 mm, 0.25 mm film). The
18
identity of products with an Agilent 5973 MSD system equipped with a FID detector
in conjugation with a 6890 N Network system. The parameters for the instrument
were such that the temperature of the oven was set to 60°C, the column flow
pressure was set to 3.0 psi, and the inlet flow temperature was set to 250°C. 1H
melting points ranges. In some cases, column chromatography was also utilized
on the oils using silica gel (60 Ǻ, 65 x 250 mesh, 500-600 m2/g) available from
analysis was performed along with column chromatography using silica plates also
B. Experimental
The aforementioned procedure in the setup section was used for this
preparation. For all the aniline derivatives, a slightly positive pressure of argon (Ar)
was inserted to the sealed reaction flask through a needle. Due to the fact that
amine aryls are so reactive compared to the other aryls, the reaction time was very
short for all derivatives. Hence, samples were taken after 1, 3, 5, 10, and 15 min.
After GC and GC/MS analysis during which the anticipated molecular weight of the
product was realized, the best time point was determined. Then the reaction was
repeated using the best time point for isolation. Finally, the reaction mixture was
isolated and the solid product was triturated using DI water, otherwise, the oil
product was re-extracted using DI water, brine and MTBE to remove succinimide.
19
The filtrate was evaporated and concentrated under reduced pressure using a
rotatory evaporator. The pure crude solid products were characterized utilizing mp
and NMR, while the pure oil products were characterized using only NMR.
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
Once the NBS dissolved into the solution, 1 equiv. of aniline (0.91 mL, 10 mmol)
was added slowly to the stirred reaction using a glass syringe. The reaction mixture
was well mixed with stirring at room temperature for 10 min. After work up with DI
water and dilution with MTBE, a sample was taken and analyzed by GC which
to a separatory funnel with the aid of MTBE and DI water. The solution was washed
with DI water three times. The organic layer was separated and washed once with
brine and dried over sodium sulfate to give 4-bromoaniline in 98.7% purity. The
concentrated product’s melting point was 50-52°C. 1H NMR (CDCl3) δ 3.2 (s, 2H),
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol)
Once the NBS dissolved into the solution, 1 equiv. of acetanilide (1.352 g, 10
mmol) was weighed and added slowly to the stirred reaction. The reaction mixture
20
was well mixed with stirring at room temperature for 15 min. After work up with DI
water and dilution with MTBE, a sample was taken and analyzed by GC which
settle for an hour. After an hour, the crystallized mixture was triturated with DI water
The aforementioned procedure in the setup section was used for this
preparation. Samples were taken after 5, 10, 15, 20, 30, 60,120,180, and 240 min.
After GC and GC/MS analysis during which the anticipated molecular weight of the
product was realized, the best time point was determined. Then the reaction was
repeated using the best time point for isolation. Finally, the reaction mixture was
isolated and the solid product was triturated using DI water, otherwise, the oil
product was re-extracted using DI water, brine and MTBE to remove succinimide.
The filtrate was evaporated and concentrated under reduced pressure using a
rotatory evaporator. The pure solid products were characterized utilizing mp and
NMR, while the pure oil products were characterized using only NMR.
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
Once the NBS dissolved into the solution, 1 equiv. of 2-methoxyphenol (1.12 mL,
10 mmol) was added slowly to the stirred reaction using a glass syringe. The
21
reaction mixture was well mixed with stirring at room temperature for 60 min. After
work up with DI water and dilution with MTBE, a sample was taken and analyzed
mixture was transferred to a separatory funnel with the aid of MTBE and DI water
water three times. The organic layer was separated and washed once with brine
and dried over sodium sulfate to afford 88% purity. The concentrated product was
an oil. 1H NMR (CDCl3) δ 3.87-3.88 (s, 3H), 5.58 (s, 1H), 6.81 (dd, 1H), 6.95-6.96
The aforementioned procedure in the setup section was used for this
preparation. Samples were taken after 5, 10, 15, 20, 30, 60,120, 180, and 240 min.
After GC and GC/MS analyses during which the anticipated molecular weight of
the product was realized, the best time point was determined. Then the reaction
was repeated using the best time point for isolation. Finally, the reaction mixture
was isolated and the solid product was triturated using DI water, otherwise, the oil
product was re-extracted using DI water, brine and MTBE to remove succinimide.
The filtrate was evaporated and concentrated under reduced pressure using a
rotatory evaporator. The pure solid products were characterized utilizing mp and
NMR, while the pure oil products were characterized using only NMR.
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
22
weighed and transferred to the flask, followed by adding 20 mL of acetonitrile.
Once the NBS dissolved into the solution, 1 equiv. of anisole (1.09 mL, 10 mmol)
was added slowly to the stirred reaction using a glass syringe. The reaction mixture
was well mixed with stirring at room temperature for 10 min. After work up with DI
water and dilution with MTBE, a sample was taken and analyzed by GC which
a separatory funnel with the aid of MTBE and DI water. The solution was washed
with DI water three times. The organic layer was separated and washed once with
brine and dried over sodium sulfate to afford 100% purity. The concentrated
product was an oil. 1H NMR (CDCl3) δ 3.45 ppm (s, 3H), 6.80-6.85 (d, 2H), 7.62-
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
Once the NBS dissolved into the solution, 1 equiv. of 1,2-dimethoxybenzene (1.27
mL, 10 mmol) was added slowly to the stirred reaction using a glass syringe. The
reaction mixture was well mixed with stirring at room temperature for 60 min. After
work up with DI water and dilution with MTBE, a sample was taken and analyzed
reaction mixture was transferred to a separatory funnel with the aid of MTBE and
DI water. The solution was washed with DI water three times. The organic layer
was separated and washed once with brine and dried over sodium sulfate to afford
23
96.6% yield. The concentrated product was an oil. For further purification, the
residue was chromatographed on silica gel (eluent: hexane- ethyl acetate = 9:1).
The progress of the purification of the product was also mentored by TLC and GC
ppm (s, 6H), 3.82 ppm (s, 3H), 6.69 (dd, 1H), 6.92 (dd, 1H), 7.03 (dd, 1H)
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
Once the NBS dissolved into the solution, 1 equiv. of 1,3-dimethoxybenzene (1.31
mL, 10 mmol) was added slowly to the stirred reaction using a glass syringe. The
reaction mixture was well mixed with stirring at room temperature for 20 min. After
work up with DI water and dilution with MTBE, a sample was taken and analyzed
reaction mixture was transferred to a separatory funnel with the aid of MTBE and
DI water. The solution was washed with DI water three times. The organic layer
was separated and washed once with brine and dried over sodium sulfate to afford
100% purity. The concentrated product was an oil. 1H NMR (CDCl3) δ 3.79 ppm
(s, 3H), 3.82 ppm (s, 3H), 6.39 (dd, 1H), 6.92-6.93 (dd, 1H), 7.39 (dd, 1H)
24
3.4) p-Bromination of 1,4-Dimethoxybenzene
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
Once the NBS dissolved into the solution, 1 equiv. of 1,4-dimethoxybenzene (1.38
g, 10 mmol) was weighed and transferred slowly to the stirred reaction. The
reaction mixture was well mixed with stirring at room temperature for 2 h. After
work up with DI water and dilution with MTBE, a sample was taken and analyzed
Therefore, one more equiv. of NBS (1.78 g, 10 mmol) was added to get the only
di-brominated product. After 60 min, the sample was taken and analyzed by GC
reaction mixture was transferred to a separatory funnel with the aid of MTBE and
DI water. The solution was washed with DI water three times. The organic layer
was separated and washed once with brine and dried over sodium sulfate to afford
100% purity. The concentrated product was an oil. 1H NMR (CDCl3) δ 3.83 ppm
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
(1.68 g, 10 mmol) was weighed and added slowly to the stirred reaction. The
25
reaction mixture was well mixed with stirring at room temperature for 30 min. After
work up with DI water and dilution with MTBE, a sample was taken and analyzed
reaction mixture was transferred to a separatory funnel with the aid of MTBE and
DI water. The solution was washed with DI water three times. The organic layer
was separated and washed once with brine and dried over sodium sulfate to afford
100% purity. The concentrated product was an oil. 1H NMR (CDCl3) δ 2.66 ppm
(s, 3H), 2.69 ppm (s, 3H), 2.72 ppm (s, 3H), 5.44-5.49 (d, 1H), 5.96-6.06 (d, 1H)
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
Once the NBS dissolved into the solution, 1 equiv. of 1,2,4-trimethoxybenzene (1.5
mL, 10 mmol) was added slowly to the stirred reaction using a glass syringe. The
reaction mixture was well mixed with stirring at room temperature for 60 min. After
work up with DI water and dilution with MTBE, a sample was taken and analyzed
reaction mixture was transferred to a separatory funnel with the aid of MTBE and
DI water. The solution was washed with DI water three times. The organic layer
was separated and washed once with brine and dried over sodium sulfate. The
concentrated product was a solid. The residue was left to settle overnight in the
refrigerator. The day after, the crystallized mixture was triturated with DI water to
26
give 5-bromo-1,2,4-trimethoxybenzene in 100% purity. The concentrated product’s
melting point was 51-52.5°C. 1H NMR (CDCl3) δ 3.83 ppm (s, 3H), 3.87ppm (s,
3H), 3.88 ppm (s, 3H), 6.57 (d, 1H), 7.07 (d, 1H) (Appendix NMR #9)
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
(1.68 g, 10 mmol) was weighed and added slowly to the stirred reaction. The
reaction mixture was well mixed with stirring at room temperature for 5 min. After
work up with DI water and dilution with MTBE, a sample was taken and analyzed
reaction mixture was transferred to a separatory funnel with the aid of MTBE and
DI water. The solution was washed with DI water three times. The organic layer
was separated and washed once with brine and dried over sodium sulfate to afford
92.4% purity. The concentrated product was a solid. The residue was left to settle
overnight in the refrigerator. The concentrated product’s melting point was 81-
84°C. 1H NMR (CDCl3) δ 3.81 ppm (s, 3H), 3.86 ppm (s, 6H), 6.16 ppm (s, 2H)
The aforementioned procedure in the setup section was used for this
preparation. Samples were taken after 5, 10, 15, and 20 min. After GC and GC/MS
analysis during which the anticipated molecular weight of the product was realized,
27
the best time point was determined. Then the reaction was repeated using the best
time point for isolation. Finally, the reaction mixture was isolated and the solid
product was triturated using DI water, otherwise, the oil product was re-extracted
using DI water, brine and MTBE to remove succinimide. The filtrate was
The pure solid products were characterized utilizing mp and NMR, while the pure
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
Once the NBS dissolved into the solution, 1 equiv. of 1-methoxynaphthalene (1.6
g, 10 mmol) was added slowly to the stirred reaction using a glass syringe. The
reaction mixture was well mixed with stirring at room temperature for 15 min. After
work up with DI water and dilution with MTBE, a sample was taken and analyzed
reaction mixture was transferred to a separatory funnel with the aid of MTBE and
DI water. The solution was washed with DI water three times. The organic layer
was separated and dried over sodium sulfate to afford 100% purity. The
concentrated product was an oil. 1H NMR (CDCl3) δ 3.93 ppm (s, 3H), 6.57-6.66
ppm (dd, 1H), 7.52 (dd, 1H), 7.57 (m, 1H), 7.66 ppm (m, 1H), 8.07 ppm (m, 1H),
28
4.2) p-Bromination of 2-Methoxynaphthalene
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
Once the NBS dissolved into the solution, 1 equiv. of 1-methoxynaphthalene (1.45
mL, 10 mmol) was added slowly to the stirred reaction using a glass syringe. The
reaction mixture was well mixed with stirring at room temperature for 5 min. After
work up with DI water and dilution with MTBE, a sample was taken and analyzed
reaction mixture was transferred to a separatory funnel with the aid of MTBE and
DI water. The solution was washed with DI water three times. The organic layer
was separated and dried over sodium sulfate to afford 96.4% purity. The
concentrated product was a solid. The residue was left to settle overnight in the
(CDCl3) δ 4 ppm (s, 3H), 7.29 ppm (d, 1H), 7.48 ppm (t, 1H), 7.59 (t, 1H), 7.79 (d,
1H), 7.82 (d, 1H), 8.19 (d, 1H) (Appendix NMR #12)
The aforementioned procedure in the setup section was used for this
preparation. A slightly positive pressure of argon (Ar) was inserted to the sealed
reaction flask through the needle. The samples were taken after 1, 5, 10, 15, 60,
90 min. After GC and GC/MS analysis during which the anticipated molecular
weight of the product was realized, the best time point was determined. Then the
reaction was repeated using the best time point for isolation. Finally, the reaction
29
mixture was isolated and the oil product was re-extracted using DI water, brine and
MTBE to remove succinimide. The filtrate was evaporated and concentrated under
reduced pressure using a rotatory evaporator. the pure oil product was
equipped with a clean magnetic stir bar. One equiv. of NBS (1.78 g, 10 mmol) was
Once the NBS dissolved into the solution was transferred slowly using to a clean,
dry 50 mL round-bottom flask equipped with a medium stir bar containing 1 equiv.
of 1,3-benzodioxole (1.15 mL, 10 mmol) while stirring. The reaction mixture was
well mixed with stirring at room temperature for 90 min. After work up with DI water
and dilution with MTBE, a sample was taken and analyzed by GC which resulted
to a separatory funnel with the aid of MTBE and DI water. The solution was washed
with DI water three times. The organic layer was separated and washed once with
brine and dried over sodium sulfate to give pure product in 98% purity. The
concentrated product was an oil. 1H NMR (CDCl3) δ 5.94-5.95 (d, 2H), 6.67 (dd,
1H), 6.90 (s, 1H), 6.95-6.98 (dd, 1H) (Appendix NMR #13)
30
Table 2. Characterization Table of p-brominated Aryl Derivatives
165.5-
4-Bromoacetanilide 91 214.06 213.1/215.1 165-169
167
4-Bromo-2-
67 203.03 202.0/204.0 34 Oil
Methoxyphenol
4-Bromo-1,2-
95 217.06 216.0/218.0 25-26 Oil
Dimethoxybenzene
4-Bromo-1,3-
94 217.06 216.0/218.0 Oil Oil
Dimethoxybenzene
2,5-Dibromo-1,4-
86.5 295.96 294/296/298 35 Oil
Dimethoxybenzene
4-Bromo-1,2,3-
95 247.09 246.1/248.1 Oil Oil
Trimethoxybenzene
5-Bromo-1,2,4-
97.7 247.09 246.1/248.1 51-53 51-52.5
Trimethoxybenzene
4-Bromo-1,3,5-
80.3 247.09 246.1/248.1 93-95 81-84
Trimethoxybenzene
31
Table 2 (continued). Characterization Table of p-brominated Aryl Derivatives
2-Bromo-1-
100 237.09 236.1/238.1 Oil Oil
Methoxynapthlene
4-Bromo-2-
90.9 237.09 236.1/238.1 80-83 80-82
Methoxynaphthalene
5-Bromo-1,3-
93 201.0 202.0/204.0 Oil Oil
Benzodioxole
32
III. RESULTS AND DISCUSSION
bromination in cyclohexane was also investigated. With the use of this solvent, the
found in the literature. Very slow conversions were most likely because of
until 20-24 h. Despite the simplicity of the operational procedure, the needs of
extensive amounts of time for the reaction to proceed in high yields presented
attained significant yields in a much shorter period. Initially, acetone attracted our
attention and it was found that in acetone the p-bromination reactions were
solvent with a high boiling point. As is evident, acetonitrile enhanced the reactivity
33
NBS and acetonitrile, the high solubility of NBS in acetonitrile allowed for a
decrease in the reaction time and increase the yield of products. In addition, the
data in Table 3 show the general applicability of the NBS/acetonitrile system for
attained in this study was acetonitrile. The table clearly shows that higher reactivity
and lower reaction times were obtained with the NBS/CH3CN system. However,
an only few examples could be collected for this table as there was not much
% GC % GC Yields
% GC Yields in
Substrate Product Yields in in
Cyclohexane
Acetone Acetonitrile
2- 4-Bromo-2-
99 (24h) 90 (15m)
methoxynaphthalene methoxynaphthalene
5-Bromo-1,3-
1,3-Benzodioxole 75.6 (3h) 93 (90m)
benzodioxole
1,3- 4-Bromo-1,3-
89 (20h) 87 (15m) 94 (20m)
Dimethoxybenzene Dimethoxybenzene
1,2,3- 4-Bromo-1,2,3-
95 (20h) 55 (30m) 95 (30m)
Trimethoxybenzene Trimethoxybenzene
1,2,4- 5-Bromo-1,2,4-
99 (20h) 50 (30m) 83 (5m)
Trimethoxybenzene Trimethoxybenzene
34
The regiospecific p-bromination reaction was carried out with a variety of
acetanilide, phenol and in most cases, their derivatives. All the p-brominated
compounds are known compounds reported in the literature and their identities
bromoanisole, the distinctive pattern is a pair of doublets, which are widely spaced.
This splitting pattern is only seen with a para-disubstituted benzene, having two
isomers. When the bromine goes to the 4 position (para) a singlet peak will appear
(see Appendix B #5). The other possible isomer (the 3-bromo isomer) would not
proves the only possibility for Br substituent is going to the 4 position. The 5-bromo
substituted compound will have a singlet signal for the methoxy groups because
35
all of the hydrogen atoms on these methoxy groups will be magnetically equivalent
due to the symmetry of the molecule. However, the obtained NMR elucidates a
doublet peak for the methoxy groups on the ring resulting in the conclusion that it
doublet peaks and two signals for methoxy groups on the 2,6-dibromo compound.
However, the obtained spectrum (#7) illustrates only a singlet signal in the aromatic
region and another singlet peak for methoxy group due to the symmetry in the
because there is only one possible isomer for this compound which is 4-bromo-
1,3,5-trimethoxybenzene with the two signals for methoxy groups and a singlet
para position, the proton ortho to the electron donating methoxy group will be
shifted slightly downfield of the other aromatics, producing a separate doublet peak
(see Appendix B #11). The ortho brominated molecule would not have this doublet
36
For monobromo-1,3-benzodioxole also if the bromine was in the 4-
position the peak for the aromatic protons would be a much more complex multiplet
peaks. On the other hand, the doublet peak in the spectrum that is shifted
downfield (6.6- 6.7 ppm) proves the para position of the bromine to the compound.
It has to be noticed that this doublet peak is separated out because it is ortho to
The NMR analysis for 2-methoxyphenol gets more complicated with two
different donating groups and four different possibilities for the brominated
compound. The 7 ppm region in the NMR spectrum (Appendix B #2) has no
this compound from the other possible isomers. The mass spectral library came in
handy and the para-brominated product matched perfectly with the mass spectral
substitution” gives a slightly easier and cleaner reaction than phenol derivatives.
37
The steric repulsion of the methyl group on oxygen's lone pairs makes it less
optimal reaction conditions. We tried the variation of the equiv. of the brominating
agent (NBS) and orders of adding the materials. For 2-methoxyphenol, the results
remained relatively low. As can be seen in Figure 12, the best result was obtained
when 1 equiv. of NBS was used. More than 1 equiv. of NBS produced a mixture of
mono- and di-brominated product. In addition, changing the order of adding the
materials could not be helpful in this case. It should be also emphasized that if the
than 60 min, the poly-brominated product would be formed. Hence, the reaction
was followed continually by GC analyses in order to stop stirring as soon as all the
substrate is almost used to avoid further conversion to more than the mono-
brominated products. Figure 12 shows the progression of GC yields for the varied
38
Figure 12. % GC yields vs. equiv. of NBS used in the preparation of 4-
bromo-2-methoxyphenol
80
70
60
50
% GC Yield
40
30
20
10
0
0 0.2 0.4 0.6 0.8 1 1.2
Equiv. NBS
and dibromo product being formed, with long reaction time. However, in the
excellent yield of 86.5% within 5min. Hence, in this case, the di-brominated product
has been reported. Surprisingly, on the other hand, the results with the other
bromination of those substrates were all successful under the same reaction
conditions. All the other di- and tri-methoxybenzene compounds gave only mono-
brominated products in the presence of 1 equiv. of NBS and short reaction times
along with high GC yields between 80.3% and 97.7%. Figure 13 shows the
39
progression of GC yields for the varied equiv. of NBS for the di-bromination of 1,4-
dimethoxybenzene.
Figure 13. % GC yields vs. equiv. of NBS used in the preparation of 2,5-
dibromo-1,4-dimethoxybenzene
100
90
80
70
% GC Yield
60
50
40
30
20
10
0
0 0.5 1 1.5 2 2.5 3 3.5
Equiv. NBS
bromination of this heterocyclic aromatic compound under the same condition was
also successful resulted in 93% yield of the 5-bromo isomer in less than 2h.
indoline have been investigated. In all cases, trying to afford a single para-
brominated isomer was unsuccessful and every time a mixture of mono- and
contain heteroatoms particularly nitrogen are notably more reactive than benzene
40
compounds and gives mixtures of di- and poly- brominated products. Moreover, all
substrates to the reaction pot. Due to the difficulties with these substrates, we
bromination.
materials, which was not successful and the temperature could not be controlled
even by the slow addition of the NBS solution to the solution of the substrate. After
that, we tried varying the reaction conditions by adding cyclohexane to the solution.
the NBS flask along with 20 mL acetonitrile. However, adding one equiv. of
cyclohexane did not make a tremendous difference in the results. We are currently
reduce the reactivity of the amine groups. It has to be mentioned we still could not
41
In order to address the question as to what is the mechanism of this
reaction, we have to mention that is not clear so far; however, some suggestions
could be proposed.
EAS
Concerted
S N2
operates this reaction that is still questionable to be EAS due to the required
conditions for this mechanism. As stated previously, utilizing Lewis acid as well as
a neutral reaction and no acidic conditions have been employed in that. The
42
mechanism of this reaction could also be presumed to be a Sn2 reaction. For this
mechanism, the negatively charged substrate could attack the bromine of NBS
with partially positive charge. Then, succinimide anion as a good leaving group
with an electronegative atom could operate the SN2 reaction. The other possibility
can be a concerted reaction, which takes place by bond breaking and bond making
in a single step. The transition step in this mechanism by moving bromine of NBS
to the para- position of the substrate and moving the hydrogen to the nitrogen of
43
IV. CONCLUSION
organic chemistry. Although various methods have been developed for the
preparation of highly practical haloarenes from activated aromatics, the goal of our
group’s research over the past years has been creating a facile and highly
chemistry. This research focused on improving the extant literature procedure for
determine what, if any, changes would happen in the regiospecificity yields of our
combination of NBS and acetonitrile affords a practical method for the synthesis of
mono- and dibromo compounds of substituted aromatics without the use of acids
or metal catalysts, thereby providing a much safer, greener, faster and more
novel use of acetonitrile to increase the polarization of the N-Br bond of NBS in
44
regioselectivity of various activated arenes. All of these factors make this reaction
This study has shown that thirteen compounds were isolated in good to
para- to the EDG on the ring in a minimal amount of time. Furthermore, the utilized
reagents in this method are cheap, easy to handle and environmentally friendly as
possible.
heterocycle compounds, which are relatively much more activated than the
–TMS substituent to see whether or not the reaction would take place at the ortho-
45
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50
VI. APPENDIX A
Substrate Product
1.1
Aniline
4-Bromoanline
1.2
Acetanilide 4-Bromoacetanilide
2.1
2-Methoxyphenol 4-Bromo-2-Methoxyphenol
3.1
Anisole
4-Bromoanisole
3.2
1,2-Dimethoxybenzene 4-Bromo-1,2-Dimethoxybenzene
3.3
1,3-Dimethoxybenzene 4-Bromo-1,3-Dimethoxybenzene
51
3.4
1,4-Dimethoxybenzene 2,5-Dibromo-1,4-Dimethoxybenzene
3.5
1,2,3-Trimethoxybenzene 4-Bromo-1,2,3-Trimethoxybenzene
3.6
1,2,4-Trimethoxybenzene 5-Bromo-1,2,4-Trimethoxybenzene
3.7
1,3,5-Trimethoxybenzene 4-Bromo-1,3,5-Trimethoxybenzene
4.1
1-Methoxynapthlene
2-Bromo-1-Methoxynapthlene
4.2
2-Methoxynaphthalene
4-Bromo-2-Methoxynaphthalene
52
5.1
1,3-Benzodioxole 5-Bromo-1,3-Benzodioxole
Indole
3-Bromoindole
Indoline 4-Bromoindoline
Pyrrole 2-Bromopyrrole
53
APPENDIX B
NMR #1 (4-Bromoaniline)
NMR #2 (4-Bromo-2-Methoxyphenol)
54
NMR #4 (4-Bromoanisole)
NMR #5 (4-bromo-1,2-dimethoxybenzene)
55
NMR #6 (4-bromo-1,3-dimethoxybenzene)
NMR #7 (2,5-Dibromo-1,4-Dimethoxybenzene)
56
NMR #8 (4-bromo-1,2,3-trimethoxybenzene)
NMR #9 (5-bromo-1,2,4-trimethoxybenzene)
57
NMR #10 (2-bromo-1,3,5-trimethoxybenzene)
58
NMR #12 (1-bromo-2-methoxynaphthalene)
59
APPENDIX C
Mass Spectrum #1 (4-Bromoanisole)
60
Mass Spectrum #2 (4-Bromo-2-Methoxyphenol)
61
Mass Spectrum #3 (2,5-Dibromo-1,4-Dimethoxybenzene)
62
Mass Spectrum #4 (2-bromo-1,3,5-trimethoxybenzene)
63
Mass Spectrum #5 (1-bromo-2-methoxynaphthalene)
64
Mass Spectrum #6 (5-bromo-1,3-benzodioxole)
65