Progress on the Synthesis of a
Symmetrical Dihydroxydibenzo-26crown-8
An Honors Thesis (HONRS 499)
By
Kyle R. Gilbert
Lynn Sousa
Faculty Advisor
Ball State University
Muncie, IN
April 25, 2007
(Expected Date of Graduation: May 5, 2007)
i
Acknowledgements
First and foremost, I would like to thank Dr. Lynn Sousa for everything he has
done to help me through these last three years of my college experience. I have
thoroughly enjoyed my experiences working with him in and outside of the lab. He has
pushed me to get the most out of my research experience and has provided me with
excellent recommendations for scholarships and graduate school applications. He has
been a wonderful mentor and exceptional role model. I appreciate all the patience and
commitment he has shown to me, and I look forward to building on the lessons I learned
under his guidance.
I would also like to thank Dr. Lang and the Louis Stokes Alliance for Minority
participation. Their generous funding has made this whole experience possible and I only
hope that they look back on my research as a good investment. Dr. Morris and the entire
Ball State Department of Chemistry have also been instrumental in my success
throughout the years. I appreciate the kindness and support I have received from
everyone in the department along with Zohreh Amoozgar, Jason Howard, and Nicole
Crutcher who I have had the pleasure of working and presenting with over the last three
years.
ii
Abstract
Crown ethers complex selected metal ions, ammonium ions, and potentially, other
electron deficient species. With proper functionalization a crown ether might sequester
and signal the presence of ions or electron deficient molecules; or from the other
perspective, complexed ions or molecules might alter the conformation and properties of
the crown ether. The target dihydroxydibenzo-26-crown-8 (l) is designed to be an
attachable jaw that can be combined with one or two chromophores to produce
fluorescent chemosensors. Progress towards the preparation of this new 26-crown-8 will
be presented. Known intermediates such as bis-I,2[2-hydroxyethoxy]benzene(2) and bis1,2 [2-(3-chloro-2-hydroxypopoxy)ethoxy]benzene(3), and a protected bis-} ,2[2-(3chloro-2-hydroxypopoxy)ethoxy]benzene(5) using Dihydropyran have been synthesized.
Our approaches to the formation of the 'jaw" crown ether (1) by reaction of (2) with (5)
will be described.
Table of Contents
Page #
Acknowledgements .............................................. , ............................... i
Abstract ......................................................................................... ...ii
Introdllction .........••....•.......•........................••.•.•.••.•••••..•••••••••.••.•.•••..•. 1
•
•
•
Crown Ethers .............................................................................. 1
Rationale for Research ................................................................... 4
Synthetic Plans ............................................................................ 7
o Scheme 1 ........................................................................... 7
o Scheme2 (The Swern Oxidation) .................................... ............ 8
o Scheme3 (THP protection) ..................................................... 10
Results and Discussion .......................................................................... 11
• Synthesis of 1,2-bis[2-hydroxyethoxyJbenzene ...................................... 11
• Synthesis of 1, 2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxy] benzene .. .......... .12
• Scheme 1................................................................................... 13
• Scheme 2 (The Swern Oxidation) .............. ........................................ 14
• Scheme 3 (THP protection) ............................................................ 15
Experimental Section ................................................... ........................ 17
• Synthesis of 1,2-bis[2-hydroxyethoxyJbenzene(2) .................................. .1 7
• Synthesis of 1,2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxyJbenzene(3) ......... .19
• Synthesis of 1,2-bis[2-(2,3-epoxypropoxy)ethoxyJbenzene(4) ... .................. .20
• Synthesis of Protected 1,2-bis[2-(3-chloro-2hydroxypropoxy)ethoxyJ
Benzene (5) ................................................................................. 21
• Preparation of the Cesium Salt (6) ..................................................................... 22
• Synthesis of the Protected Dihydroxydibenzo-26-Crown-8(7) ............... ...... 22
References ........................................................................................ 24
Appendix A (
IH
and 13C NMR) ..............................................................25
Introduction:
Crown Ethers
Crown ethers are heterocyclic chemical compounds that, in their simplest form,
consist of repeating -CH2CH20- units. These compounds were first discovered in 1967
as an unexpected byproduct of a synthesis reaction performed by Charles Pedersen 7.
While trying to prepare a complexing agent for divalent cations by linking two Catechol
molecules through one hydroxyl group on each molecule, he was surprised to isolate a
byproduct that bound or complexed with potassium cations but had no ionizable hydroxyl
group. He pursued the research further by creating thirty-three ofthese "cyclic
polyether" compounds to discover their unique ability to complex with metal cations and
electron-deficient species due to the inwardly facing oxygen atoms that are ideally
situated to coordinate with a cation in the interior of the ring. He named them "crowns"
because when this special group of heterocycles binds to cations the complex resembles a
crown sitting on a head. It was initially believed that the stoichiometry of the complexes
was one molecule of polyether per single ion regardless of the valence; however, it has
since been discovered that a few very large crowns can have two complexed cations at
Figure 1: an 18-crown-6 compound
showing non-covalent interactions and
complexation of metal ion with inwardly
facing oxygen atoms. Generally only one
ion will complex with one crown
compound at a given time.
2
Another important feature of the crown complexes involves their selective
complexation ability. Because of this unique property, particular ions can be targeted
while creating crown ethers based on the size of the cavity of the crown, diameter of the
target cation, number of donor atoms in the crown, and charge number of the target
7
cation
•
This molecular recognition behavior has helped bridge one of the fundamental
gaps between biological reaction and artificial chemical reaction. Since Pederson's
discoveries many investigations on the analyses of these structures, their characteristics,
as well as applications have been developed.
The United States Patent and Trademark Office currently lists twenty-nine patents
involving crown ether compounds ranging from 1974-2006. The earliest patents used
crown ethers as catalysts for the polymerization of conjugated dienes, lactam, and 2pyrrolidone and caprolactam JO • Through what is known as "host-guest" chemistry,
scientists have been able to develop simple organic compounds that mimic enzymatic
activity as phase transfer catalysts (PTC's). PTC's facilitate the migration of a particular
chemical component from one phase into another phase in a heterogeneous system. For
example, a specific chemical component could be soluble in one phase but insoluble in
the other unless the phase transfer catalyst is present. In the case of crown ethers, even
though the interior of the ring is highly hydrophilic, the exterior of the ring is
hydrophobic. The result is that the complexed cation can become soluble in non-polar
solvents4 •
More recent developments in crown ether technology have been focused on
crown ethers as chemical sensors or "chemosensors." By attaching specialized functional
3
groups to the crown ether compounds, target cations bonded through non-covalent
interactions will produce a change in light absorption or fluorescence, which can be
monitored and measured. A key requirement of chemosensor function is that the cation
binding occur reversibly (non-covalently). This allows cation concentration to be
measured at equilibrium by optical detection of either the chemosensor-bound species or
the cation-free chemosensor. It also allows for continuous measurements to be made
with dynamic optical response to changing cation concentration2 •
A current U.S. Patent exists for a fluorescent ion-selective diaryldiaza crown ether
that is primarily useful for detection and quantitation of alkali-metal ions in aqueous
solution. Such indicators are useful for measuring ions in extracellular spaces; in
vesicles; in vascular tissue of plants and animals; biological fluids such as blood and
urine; in fermentation media; in environmental samples such as water, soil, waste water
and seawater; and in chemical reactors8.
Another example of chemosensor technology was implemented at the NIEHS
Marine and Freshwater Biomedical Sciences Center at the University of Miami where
several crown ethers were attached to fluorescent molecules used to monitor the level of
harmful marine toxin saxitoxin from red tides. For economic and ethical reasons, these
fluorescent crown ether sensors were meant to replace prior methods including biological
assays and expensive and time-consuming analytical equipment5 •
Abiotic chemosensors are being tailored for a vast amount of target molecules,
and their physical properties engineered to meet specific sensor requirements. These are
added advantages compared to biotic receptors that are sensitive to pH, oxidizing agents
and heat, which may be necessary conditions for some analytical devices2 • Currently,
4
extensive research is being carried out into the development of large supramolecular
chemosensor compounds that are highly specific and have extensive signaling
attachments and have oxygen donor atoms replaced with "softer" bases such as nitrogen,
sulphur, and phosphorous 7•
Rationale for Research
Our target molecule is a Dihydroxydibenzo-26-Crown-8(1). It is our belief that
our molecule could be used as a chemical sensor for important ions, or electron deficient
pi systems. Based on the design of the molecule, the crown would collapse like ajaw
when complexed with a specific ion. Fluorescent molecules would be attached at the
hydroxyl backbone of the crown and would emit fluorescence of some kind as a result of
the bending induced after complexation with a specific ion. This fluorescence could be
measured under ultraviolet light and measured in a UV -visible spectrometer. The
conformational changes induced after complexation may also be observed with carbon-I 3
NMR. By being able to measure this interaction between our crown and its specific
target ion, we will be able to measure ion concentrations in a non-invasive manner, which
would be less time-consuming, more cost effective, and less detrimental to the solution
being observed than with current methods. We have proposed a few methods of
producing these results from our crown.
5
Single fluorescent molecule attachment
One fluorescent molecule would be attached to both hydroxyl groups of the
crown. As the crown clamps in the presence of positive metal ions or organic compounds
bearing a positive charge, the molecule attached at the hydroxyl groups would flex and
emit altered fluorescence or absorb light at a different wavelength allowing the
concentration of the electron deficient compound to be determined by fluorescence
measurements or UV spectra analysis.
Induced Excited Dimer Formation
Separate fluorescent molecules would be attached at each hydroxyl group of the
crown. When the crown collapses in presence of an electron deficient molecule or a
cation, the fluorescent molecules would be drawn together, forming an excited dimer,
6
which may emit fluorescence that can be viewed in the visible spectrum or measured in
Carbon-I3 NMR.
Displacement of a Quencher
With one fluorescent molecule attached to both hydroxyl groups, large atoms such
as Cesium would quench the fluorescence of the molecule. When smaller atoms such as
Potassium displace these larger atoms, the crown would bend more and flex the molecule
attached at the hydroxyl backbone, which could induce changes in fluorescence and the
carbon-13 NMR. This would allow us to distinguish between ions in a solution
consisting of multiple electron deficient particles.
7
Synthetic Plans
Our plan for the Dihydroxydibenzo-26-crown-8(l) synthesis was to take a multistep approach starting from Catechol and progressively adding extensions to the 1,2
hydroxyl groups. From this method, we would build a large two-armed molecule that
would be closed off to form a ring in a final step.
Scheme 1
OH
~/
O'Na+
_2_N_aO_H_ _-J......
~OH
ceO
b
(2)
(3)
O
+2
~O- Na+
EtOH
CI~OH
1\
~O
OH
~O\..JOH
(2)
OH
r-\
I
~(
OH
+
~
0
o~
L-I
SnCI4
CI
..
-H+
r-\/
I
.. (X0 °
\
bOO
L-I \
I
OH
I
CI
CI
(3)
(4)
8
a
I~.~
~/o
~
+
'b)
(4)
:r
I~OO~
AOO
'-I
HO 0:0
/<\
a
I
"--.J'
6
(2)
In our initial attempt to develop the Dihydroxydibenzo-26-Crown-8( 1), we
reacted 1,2-bis[2-hydroxyethoxy]benzene(2) with Epichlorohydrin to create 1,2-bis[2-(3chloro-2-hydroxypropoxy)ethoxy]benzene(3). We then reacted compound (3) with a
strong base (KOH) to develop I ,2-bis[2-(2,3-epoxypropoxy)ethoxy ]benzene(4). Similar
to the reaction with Epichlorohydrin to form compound (3), we used Tin(IV) Chloride as
a catalyst to react compound (2) with compound (4) in hopes of forming our target
molecule, compound (1). To date, our research group has made a number of attempts
with different sets of conditions. A recent approach has given preliminary indications of
possible success),
Scheme 2 (The Swern OxidationyI
o
OH
o
+
CI)-I(CI
er
I\~
o
0
I
(3)
~
0
0
CI CHCI
2 2
CI
0
'---I ~
OH
I\~
~
-78°C
Et3N
(YO
0
CI
~O
0
CI
'---I~
o
9
o
or-\~
0
CI
ce
I
~
HO
+
HO
O\_'p~CI
r-\
O~
O~
"--.I
o
(2)
A
OH
!J
rOOl
rOOl
ce
, """ o
~
0)0
I
°
o
~O
O~
Y
o
~
NaSH
4
or LiAIH4
...
0)0
,
ce
, """
o
~
o
~o
y
°
~
o~
OH
(1)
As a result of the 1,2-bis[2-(2,3-epoxypropoxy)ethoxy]benzene(4)'s stubbornness
to react, we attempted to create a more reactive molecule in order to add the 1,2-bis[2hydroxyehtoxy]benzene(2) to complete the crown synthesis. We decided to utilize a
Swern oxidation on compound (3) to form a more reactive a-chlrorcarbonyl compound.
Unfortunately, we discovered the a-chlrorcarbonyl compound was too reactive and
formed polymers I.
10
Scheme 3 (Protection with rHP)
2
0 ___
:0
°
-J"_
Ts_OH_ _
o
CX' ;---\~
CHlCl l
0
0
CI
b
O,-_-,,Py'
#
(5)
c::(
1\
...
I ::
0
(6)
oc,'
oc
~
+
s
Q
A0,\
(0
- - - - - l.......
THF
°
°
D
C(o
°
"-.-0y oJ
o
In our latest approach, we decided to try protecting the hydroxyl groups of the
1,2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxy ]benzene(3) using Dihydropyran to
(7)
11
prevent any temptation towards a polymerization reaction. As previously proposed, we
would then react the protected compound with 1,2-bis[2-hydroxyethoxy]benzene(2) to
create the dibenzodihydroxy-26-crown-8( I). The 1,2-bis[2-hydroxyethoxy]benzene(2)
would first be reacted with CsOH to form a salt compound (6) that would potentially help
form the crown by using the cesium ions to complex with the crown as a template to
induce folding.
We decided to use Dihydropyran because many other alcohol protecting groups
such as MOM and MEM compounds required the use of strong base to be attached,
which could possibly reform the diepoxide compound we attempted in scheme 16.
Dihydropyran is attached using an acid (TsOH) catalyst3, which is more compatible with
our compound. Our only concern with using Dihydropyran was adding chiral centers to
the compound, increasing the number of stereoisomers, and creating confusion in the
NMR.
Results and Discussion:
Synthesis of l,2-bis[2-hydroxyethoxyJbenzene(2)
OH
aN~
(Y' _2_Na_O_H_ _...... (Y'. + 2 CI~OH
V OH EtOH
Vo' Na+
12
In a typical reaction, (2) was recovered giving a 29.3% yield. Yields from this
experiment ranged from 25-30% in most cases with a melting range from 77-83°C.
Some possible reasons for our low yields include oxidation of the reagent catechol while
changing the reaction apparatus. We also discovered that the 1,2-bis[2hydroxyethoxy]benzene(2) product was slightly soluble in water and may have been lost
during the workup. Some product was recovered from the waste material by redissolving it in Ethyl Acetate, but not enough could be extracted to significantly improve
our final yield. Proton and Carbon-I 3 NMR were taken upon recrystallization of our
product. (See Appendix A)
Synthesis of },2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxyJbenzene(3)
ceO OH
1"\
I
h,O
(2)
2~
0 ..........
o~
CI
'---I
+
$ nC1 4
...
-H+
..
ceO
;--\ I
o
(3)
0
OH
I
°
\
0
'---I \
I
I
CI
CI
OH
After all reagents were added to the round-bottom flask and allowed to reflux at
70°C, thin-layer chromatography (TLC) was taken every 30 minutes and developed in
5% Methanol in Dichloromethane until the I ,2-bis[2-hydroxyethoxy ]benzene(2) had
faded. The solution was then worked up according to the experimental protocol. The
remaining product (3) was a golden syrupy compound that produced a crude yield of
13
approximately 83.5% in most cases. We found that it was crucial to stir the 1,2-bis[2hydroxyethoxy]benzene(2) for at least 4 hours under argon gas to remove all traces of
oxygen and water before reacting with Tin(IV) Chloride catalyst and Epichlorohydrin.
Otherwise, yields dropped significantly. Proton and Carbon-13 NMR were taken of our
product. (See Appendix A)
Scheme 1
Synthesis of 1, 2-bis[2-(2, 3-epoxypropoxy)ethoxyjbenzene(4/
OH
0
0
b :0
;-\~
°
CI
2KOH
0
Cl
EtOH
"--I~
(3)
OH
..
r.
;-\~
0:0
0
(CI
bOO
Cl
"--I~
O·
0
..
;-\~
0:0
0
bOO
"--I
'-v
(4)
0
To protect this reaction from absorbing water, a Calcium Chloride drying tube
was placed on top of the round-bottom flask. TLC was taken every 15 minutes and
developed in 5% Methanol in Dichloromethane until the 1,2-bis[2-(3-chloro-2hydroxypropoxy)ethoxy]benzene(3) had faded. After the product was worked up, the
remaining solvent was evaporated under high vacuum without heat. Heating the 1,2bis[2-(2,3-epoxypropoxy)ethoxy ]benzene(4) resulted in polymerization. In a typical
reaction, 6.27g (I9mmol) of crude product was recovered resulting in a 95% yield l .
Proton and Carbon-I 3 NMR were taken of our product. (See Amoozgar, 2006-2007)
14
Synthesis ofdihyroxydibnezo-26-crown-8(l/
...
We observed 1,2-bis[2-(2,3-epoxypropoxy)ethoxy]benzene(4) to be much less
reactive than expected. After several attempts we were unable to react (4) without
polymerization. The synthesis of the dihyroxydibnezo-26-crown-8( 1) was unsuccessful
by this method I. New reaction conditions are being investigated by a research colleague.
Scheme 2
The Swern Oxidation l
OH
I
o
0
CI~CI
15
The a-chlrorcarbonyl compound created from the Swem oxidation was found to
be extremely reactive. We were unable to control our reaction and prevent
polymerization. This method also failed to produce our target molecule, the
dihyroxydibnezo-26-crown-8(1) 1.
Scheme 3
THP protection
o
OH
r-\/
CXO
1#
I
0
\ CI
+
/1
0,,---/\
,0
'I
TsOH
0
I
(3)
OH
This being our first attempt at this experiment, we were a bit uncertain about what
to expect. We based our protocol primarily on our source from the Journal of Organic
Chemistr/. We kept mole ratios and procedures the same from the original protocol
described in the article. We were able to recover 6.221g of a syrupy crude product which
produced a crude yield of 116%. From a proton and carbon-l 3 NMR prediction program
available on ChemDraw, we were able to approximate our absorption peaks from our
own NMR spectra of our crude product (See Appendix A). By comparing our
experimental data with the predicted results from the ChemDraw software, we were fairly
confident the reaction was successful.
16
One possible explanation for this excessive yield would be the presence of extra
solvent that may not have been completely removed during the rotary evaporation. Based
on the results described in the article, we assumed a 95% yield for our calculations in the
next step of the reaction. The crude product was placed on an oil pump overnight to
remove any traces of excess solvent and/or water.
Synthesis of the Protected Dihydroxydibenzo-26-Crown-8(7)
Q
~
01\O'Cs
c:c
#'
(6)
o
+
<
o·c.·
'---I
+
CI
Q
o
~I\
0
0Y'll
CIO
(0~o~
o
0
~
>
o~
"---I
o
0
0
0
------~~- ~
THF
"'-.0
(5)
y
~
oJ
(7)
6
Once again, we collected a yield of crude product above 100%. After the solvent
was removed using rotary evaporation and vacuum pumping, 6.833g of slush remained.
Proton and Carbon-I 3 NMR were taken and again compared with the predicted NMR
produced from the ChemDraw software. We observed several multiplet peaks in the
proton NMR, which were difficult to distinguish. We saw evidence that there was 1,2bis[2-hydroxyethoxy]benzene(2) and the protected 1,2-bis[2-(3-chloro-2hydroxypropoxy)ethoxy]benzene (5) in our solution, but no distinguishing peaks that
would imply the presence of the dihydroxydibenzo-26-Crown-8(7). Based on the
17
predicted spectra from the ChemDraw software, there are many similarities between the
spectra of compound (5) and compound (7). (See Appendix A)
Our plans for the future are to perform chromatography on the solution to
remove as much of compound (2) along with any other side products that may be present.
We will then re-analyze the solution using proton and Carbon-I 3 NMR to better confirm
or deny the presence of the protected crown (7).
Experimental Section:
Reagents and Materials:
Sodium Hydroxide, Absolute Ethanol, Catechol (99+%), 2-Chloroethanol (99%),
Ethyl Acetate (99.5%), Sodium Sulfate (Anhydrous), Tin(IV) Chloride (99.995%),
Epichlorohydrin (99+%), Ethyl Ether, Chloroform-D (+0.05% VN TMS), KOH,
Dichloromethane (Low Water), 3,4-Dihydro-2H-pyran (97%), Sodium Bicarbonate,
Toluene,p-Toluenesulfonic Acid Monohydrate (98.5+%), Cesium Hydroxide
Monohydrate, (min 90%).
Synthesis of 1,2-bis[2-hydroxyethoxyJbenzene (2)
Sodium Hydroxide (24.012g, 600mmol) was added to 300mL of Absolute
Ethanol (abs. EtOH) in a 1000mL 3-neck round-bottom flask. The flask was slightly
heated using a heating mantel with the variac setting at 15. Argon gas was passed over
18
the system for one hour to purge the system of oxygen. Catechol (27.447g, 250mmol)
was then added to the system, forming a chunky, white precipitate in a dark green
solution. 2-Chloroethanol (40mL, 600mmol) was dissolved in 50mL of Absolute Ethanol
and added drop wise to the reaction mix. The solution was then stirred and allowed to
reflux (variac 30) for 36 hours under a positive pressure of argon gas forming a dark
brown solution and a white salt precipitate. The Absolute Ethanol was then distilled off
and the remaining sticky, brown product was left to dry overnight under argon. The dried
product was then washed with 400mL of Ethyl Acetate (EtOAc) and 100mL of 1M
NaOH. Using a 1000mL seperatory funnel, the bottom layer was removed. The top
(EtOAc) layer was then washed with 100mL of 1M NaOH, 100mL of distilled water, and
100mL of saturated brine solution. The remaining golden solution was dried with several
scoops of anhydrous Sodium Sulfate and the excess EtOAc solvent was boiled off using a
rotary evaporator. The product was left overnight to recrystallize in approximately
100mL of the remaining EtOAc solvent. The crystallized product was then removed
using vacuum filtration on a Buchner funnel. Yields from this experiment ranged from
25-30% in most cases with a melting range from 77-83 °C. Proton and carbon-13 NMR
were taken of the recrystallized product. (See Appendix A)
NMRdata:
H NMR(CDCh): (5 3.402-3.931 (4H,m), 4.049-4.087 (6H,m), 6.874-7.002 (4H,m).
l3 C
NMR (CDCh): (561.169, 71.607, 114.179, 122.237, 148.955
19
Synthesis oj },2-bis{2-(3-chloro-2-hydroxypropoxy)ethoxyJbenzene (3)
1,2-bis[2-hydroxyethoxy]benzene(2) (1.995g, 10mmol) was dried under argon for
4 hours, while maintaining a temperature between 70-80'C. 4-5 drops of Tin(IV)
Chloride were then added to the flask. After the Tin(IV) Chloride was added,
Epichlorohydrin (2.5mL, 32mmol) was added drop wise to the reaction mix. As the solid
dissolved and stirred, the solution was allowed to react under argon for 2 hours. The
reaction was monitored using TLC. The Tin(IV) Chloride catalyst was then deactivated
using 15mL of distilled water and the new 1,2-bis[2-(3-chloro-2hydroxypropoxy)ethoxy]benzene(3) product was dissolved in 70mL of Ethyl Ether and
washed three times with 20mL of 8% NaHC03 , 20mL of distilled water, and 20mL of
saturated brine solution, and then separated using a small seperatory funnel. The
remaining Ethyl Ether layer was dried using several scoops of anhydrous Sodium Sulfate.
The dried solution was then decanted and rotary evaporated to remove the Ethyl Ether
and excess Epichlorohydrin. The remaining product was a golden syrupy compound that
massed 3.221g (8.4mmol). Yields from this experiment were approximately 83.5% in
most cases. Proton and carbon-13 NMR were taken of the product. (See Appendix A)
NMRdata:
H NMR(CDCh): 03.156-3.236 (1.6 H,m), 3.526-3.776 (11.15 H,m), 3.777- 3.895
(4.2 H,m), 3.922-4.005 (2.4 H,m), 4.082-4.102 (3.8 H,m), 6.786-6.891 (4 H,m).
l3 C
NMR (CDCh): 045.607,67.951, 70.108, 70.330, 72.532, 113.642, 121.713
20
Scheme 1
Synthesis oj 1, 2-bis[2-(2,3-epoxypropoxy)ethoxyJbenzene (4/
1,2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxy]benzene(3) (7.66g, 20mmol) was
added to a 250mL round-bottom flask. Absolute Ethanol (100ml) was added to the flask
and stirred in an ice bath for 10 minutes or until all of the 1,2-bis[2-(3-chloro-2hydroxypropoxy)ethoxy]benzene(3) had dissolved. To protect the reaction from
absorbing water, KOH (2.60g, 40mmol) was added to the round bottom flask. After 2-3
hours, the reaction mix was transferred to a 200mL flask. 30mL of distilled water was
then added and the solution was monitored using pH paper. The reaction mix was
neutralized using 1% HCL until pH reached approximately 6-7. The reaction mixture
was then transferred to a seperatory funnel and 1,2-bis[2-(2,3epoxypropoxy)ethoxy]benzene (4) was extracted with 100ml of Ethyl Ether. The
product was washed three times with 20mL of distilled water, once with 20mL of brine
solution, and then dried using several scoops of anhydrous Sodium Sulfate. Crude
product was transferred into a 250ml round bottom flask and solvent evaporated under
high vacuum without heat. 6.27g (19mmol) of crude product was recovered producing a
yield of 95%1. Carbon-13 and proton NMR were taken of our product. (See Ammozgar,
2006-2007)
NMRdata:
HNMR(CDCh): 02.562-2.567 (1.75 H,m), 2.705-2.717 (1.75 H,m), 3.03-3.108
21
(1.7 H,m), 3.419-3.463 (2.2 H,m), 3.556-3.747 (4 H,m), 3.7856-3.821 (5.8 H,m), 4.0854.18 (4 H,m), 6.850-6.874 (4 H,m).
I3C NMR (CDCb): () 44.293,50.930,68.999, 70.017, 71.469,115.057, 122.107, 149.070
Scheme 3 (THP protection)
Synthesis ofProtected 1, 2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxyJbenzene (5)
1,2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxy]benzene(3) (3.735g, 9.75mmol)
was stirred in a round-bottom flask at O°C in 90mL of Dichloromethane. Dihydropyran
(7.2mL, 79mmol), and TsOH (0.017g, 0.089mmol) were then added to the reaction flask
and allowed to stir. After 10 minutes, the ice bath was removed from the flask and the
solution was allowed to react at room temperature overnight. The solution was then
washed with equal parts of Ethyl Ether and a solution made from 40ml brine solution,
40ml saturated Sodium Bicarbonate solution, and 80ml of distilled water. The organic
layer was saved and washed twice with 40mL of brine solution. The solution was then
dried with several scoops of anhydrous Sodium Sulfate in 100mL of Toluene. Finally,
the solution was rotary evaporated to remove excess solvent. The final product massed
6.221g, which produced a yield of 116%. Carbon-13 and proton NMR were taken. (See
Appendix A)
22
NMRdata:
H NMR(CDCb):
.s 1.19-1.74 (15.4 H,m), 3.68-4.15 (29 H,m), 3.7856-3.821 (5.8 H,m),
4.78-4.95 (2 H,m), 6.88-6.90 (4 H,m).
I3C NMR (CDCh):
.s 19.486,25.55,30.86,44.83,62.759, 70.28, 71.40, 75.27, 75.59,
76.85,98.81,115.13, 121.78, 129.12, 149.13
Preparation of the Cesium Salt (6)
In a three-neck round-bottom flask, 1,2-bis[2-hydroxyethoxy]benzene(2) (1.845g,
9.3mmol) was added to Cesium Hydroxide monohydrate (3.136g, 18.6mmol) in
approximately 100mL of Toluene. The solution was boiled on the rotary evaporator until
most of the Toluene had been removed. The remaining solvent and water was removed
using a vacuum pump. A white solid remained as our cesium salt compound (6).
Synthesis ofthe Protected Dihydroxydibenzo-26-Crown-8 (1)
The protected 1,2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxy ]benzene(5) (5.1 06g,
9.3mmol) was dissolved in low water THF and added to the same three-neck roundbottom flask containing the cesium salt compound (6). The solution was then heated to
reflux and left under argon gas for three days. The THF solvent was then boiled offusing
the rotary evaporator. The remaining brown, syrupy compound was washed with 50mL
of distilled water and 50mL ofDichloromethane. The Dichloromethane layer was then
separated and saved, while the water layer was washed three times more with 50mL of
23
Dichloromethane to extract any remaining product still in solution. The combined
Dichloromethane layers were then dried twice with several scoops of anhydrous Sodium
Sulfate. After drying, all solvent was removed using the rotary evaporator and vacuum
pump. Proton and carbon-13 NMR were taken. (See Appendix A)
NMRdata:
H NMR(CDCb): &1.53-1.70 (12 H,m), 3.71-4.16 (26 H,m), 4.79 (2 H,m)
6.91-6.97 (4 H,m).
\3C NMR (CDCb): & 19.48,25.43,30.67,44.79,62.68,68.77,70.28,71.99,98.83,
115.92, 122.54, 149.15
24
REFERENCES
1.) Amoozgar, Zohreh. Lab Manual. Ball State University. (2006-2007).
2.) Bell, T.W.; Hext, N.M.; The Royal Society a/Chemistry. 33,589-598, (2004).
3.) Bernady, K.F.; Floyd, M.B.; Poletto, J.F.; Weiss, MJ.; J. Org. Chern., 44, 1438,
(1979).
4.) Cram, DJ.; Cram, J.M.; Science. vol. 183,4157, (1974).
5.) Gawley, R.E.; J. Am. Chern. Soc., 124 (45), 13448-13453, (2002).
6.) Greene, T.W.; Wuts, P.G.; "Protection for the Hydroxyl Group, Including 1,2- and
1,3-Diols: Ethers." Protective Groups In Organic Synthesis: Second
Edition. John Wiley & Sons, Inc. New York, NY. (1991). 14-86.
7.) Hiraoka, Michio; Crown Ethers and Analogous Compounds: Studies in Organic
Chemistry (45). Elsvier Science Publishers B.V; Amsterdam, The Netherlands,
(1992).
8.)Kuhn, M.A.; U.S. Patent 5,516,864, (1996).
9.)Pedersen, CJ.; J. Am. Chern. Soc., 89:26, 7017-7036, (1967).
10.) United States Patent and Trademark Office Full-Text and Image Database. 13 April
2007. http://patft.uspto.gov/netacgi/nph-Parser?Sectl =PT02&Sect
2=HITO FF&u=%2Fnetahtml%2FPTO%2Fsearch-adv .htm&r=O&p= 1&f=
S&I=50&Query=ttl%2F%28crown+and%28ether%29%29%OD%OA&d=PTXT.
25
Appendix A (lH and 13C NMR)
Page #
1,2-bis[2-hydroxyethoxy]benzene(2) .......................................................... xx
(I H NMR, Full Spectrum with Integration)
1,2-bis[2-hydroxyethoxy]benzene(2) .......................................................... XX
(J3 C NMR, Full Spectrum with Labeled Peaks)
1,2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxy ]benzene(3) ................................. xx
eH NMR, Full Spectrum with Integration)
1,2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxy ]benzene(3) ................................ XX
(I3 C NMR, Full Spectrum with Labeled Peaks)
Protected 1,2-bis[2-(3 -chloro-2-hydroxypropoxy)ethoxy]benzene (5) .................... XX
(Predicted IH NMR Spectrum from ChemDraw Software)
Protected 1,2-bis[2-(3 -chloro-2-hydroxypropoxy)ethoxy ]benzene (5) .................... XX
(IH NMR, Full Spectrum with Integration)
Protected 1,2-bis[2-(3-chloro-2-hydroxypropoxy)ethoxy ]benzene (5) .................... XX
(13 C NMR, Full Spectrum with Labeled Peaks)
Protected Dihydroxydibenzo-26-Crown-8 (7) ................................................ XX
(Predicted IH NMR Spectrum from ChemDraw Software)
Protected Dihydroxydibenzo-26-Crown-8 (7) ................................. , .............. XX
NMR, Full Spectrum with Integration)
eH
Protected Dihydroxydibenzo-26-Crown-8 (7) ............................................... XX
(13 C NMR, Full Spectrum with Labeled Peaks)
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