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Enantioselective Epoxidation of 1,2- Dihydronapthalene and Styrene

By Use of Jacobsens Catalyst


Johnathan Harvell
Undergraduate of Chemistry, Colorado State University, Fort Collins, CO, 80521, United States
CHEM 440 L01
13 0ctober 2015

Abstract

The purpose of this experiment was to demonstrate and understand the asymmetric synthesis
of enantioselective epoxidation of 1,2-dihydronapthalene and styrene by use of synthesized Jacobsens
Catalyst. In this experiment, the enantioselective epoxidation for 1,2 dihydronapthalene and synthezied
Jacobsens Catalyst were found to have percent yields of 15.2% and 83.3% respectively. The alkenes
were found to have % ee of 18.1% (styrene) and 80.8% (1,2-dihydronapthalene). 1H-NMR was used to
confirm the synthesis of each epoxide and catalyst by use of CDCl3 (l) and the use of the chiral shift
reagent (Eu(hfc)3 (s). As a result of the experiment, it was found that the enantioselective epoxidation of
the 1,2-dihydronapthalene was more hindered than styrene by the evident difference in %ee due to
lower torsion of carbon ring bonds in correlation to the plane of attack of the catalyst.
Introduction

Epoxidation of alkenes have typically been accomplished by the use of peroxy-acids, which are
commonly known as olefin epoxidations.1 Olefin epoxidations require that an alcohol group be present
on an alkene to perform the epoxidation, which causes the product of the epoxidation to form a racemic
mixture based position of catalysts attack on the alkene during the reaction; however, with the used of
metal based catalyst, a degree of enantioselectivity of the epoxide product can be obtained due to the
coordination of the alkyl alcohol group to the metal-based center of the present catalyst used for the
reaction.1 For this epoxidation experiment, the metal-based catalyst used is commonly known as the
Jacobsens Catalyst; the manganese center of the Jacobsens catalyst is very reactive in the presence of
atmospheric oxygen, which allows the enantioselective epoxidation of alkenes to be performed as seen
demonstrated below in Figure 1:2

Figure 1: Mechanism of Jacobsen Catalyst Alkene Epoxidation

For the epoxidation of this experiment, Jacobsens catalyst will be synthesized in the laboratory
via the following reaction below in Figure 2:3

Figure 2: Experimental Synthesis Reaction of Jacobsen's Catalyst

and then used to perform an enantioselective epoxidation of 1,2-dihydronapthalene and styrene to


determine the high enantiomeric purity of product; the confirmation of product will be determined by
the use of TLC and 1H-NMR with CDCl3 (l) with the chiral shift reagent (Eu(hfc)3. The epoxidation reactions
that will be performed in this experiment can be seen demonstrated below in Figure 3-4:

Figure 3: Enantioselective Epoxidation of 1,2-Dihydronapthalene with (R,R)-Jacobsen's Catalyst Reaction


Figure 4: Enantioselective Epoxidation of Styrene with (R,R)-Jacobsen's Catalyst Reaction

Experimental Procedure 23456

Synthesis of Jacobsen Catalyst

In a 150 mL beaker 50 mmol of L-(+)-Tartrate was dissolved in 25 mL of water, stirred, and then
100 mmol of racemic 1,2-diaminocyclohexane was added slowly to the beaker in one portion. With
dissolution of the solids completed, 5 mL of glacial acetic acid was added to the mixture, then the
mixture was placed in an ice water bath of 45 minutes. The solid product was obtained by suction
filtration, and the product was washed with 5 mL of cold water and multiple portions of methanol.
Recrystallization of the product was achieved by dissolution in hot water, filtered by gravity filtration,
and cooled to room temperature. The recrystallized product is then placed back into the ice bath until
further crystallization is induce. The crude product is then dried.

4.2 mmol of the dry solid [(R,R)-1,2-diaminocyclohexane mono-(+)-tartrate salt] is placed into a
100 mL round bottom flask equipped with a stir bar with 1.16 g of K2CO3 (s) and 6 mL of water. The
mixture is stirred to dissolution and 22 mL of ethanol was then added. The mixture is then heated to
reflux; upon reaching reflux, 8.5 mmol of 3,5-di-tert-butylsalicylaldehyde dissolved in 10 mL of ethanol is
added to the mixture via Pasteur pipette through the reflux condenser. Reflux is continued for an
additional 30 minutes. After reflux, 6 mL of water is added to the mixture and cooled in an ice water
bath for 20 minutes. The solid product is then collected by suction filtration and washed with 5 mL of
ethanol. The solid is then dissolved in 25 mL of CH2Cl2 (l) , washed with 10 mL of water, and 5 mL of
saturated aqueous NaCl. The mixture is then separated into aqueous and organic layer, and the organic
layer is dried over Na2SO4 (s). The organic layer is then decanted and CH2Cl2 solvent is removed from the
mixture by rotary evaporation. The crude products, [(R,R)-N,N-Bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediamine], specific rotation is analyzed by use of 250 mg of the crude solid dissolved in 10 mL
of CH2Cl2 (l) and confirmed by 1H-NMR.

1 g of the crude product is placed in a 100 mL three-neck round bottom flask with a magnetic
stirrer and dissolved in 25 mL of absolute ethanol. The mixture is heated to reflux, and then two
equivalents of Mn(OAc)2 4H2O are added to the flask. Reflux is continued for 20 minutes and air is then
allowed to flow slowly into the flask via a needle through one of the flask neck stoppers. Air is allowed
to flow until all yellow solid present in the flask is dissolved, and then air is removed from the flask;
three equivalent of LiCl(s) is added to the mixture and reflux is continued for an additional 20 minutes.
The solution is transferred to a clean, 100 mL round bottom flask and the solvent is removed by rotary
evaporation. The crude solid is then dissolved in 25 mL of CH2Cl2 (l), washed with 10 mL of water, and 5
mL of saturated aqueous NaCl. The organic phase is dried with Na2SO4 (s) in 30 mL of heptane. CH2Cl2 (l)
solvent is removed by rotary evaporation and cooled in an ice bath for 30 minutes. The catalyst is
obtained by suction filtration and air dried.
Enantioselective Epoxidation of 1,2-Dihydronapthalene and Styrene

5 mL of Na2HPO4 (l) is added to a mixture of 12.5 mL of Clorox bleach, 1 drop of 1M NaOH (aq), 500
mg of 1,2-dihydronapthalene (l), 50 mL CH2Cl2 (l) and 244 mg (10 mol %) of dried catalyst in a 50 mL round
bottom flask. The mixture is stirred for 60 minutes at room temperature with the septum of the flask
covered. The reaction is checked for completion by TLC with 30:70 mixture of CH2Cl2 (l): heptane (l); the
TLC is visualized by use of UV light and ceric stain. 50 mL of hexane (l) is added to the reaction mixture
and transferred into a separatory funnel. The organic layer is separated, washed with 20 mL of saturated
NaCl (l), and then dried over with MgSO4 (s). The solution is then gravity filtered into a clean, 100 mL
round bottom flask, and TLC is used to confirm presence of desired epoxide. The solvent is then
removed from the crude product by rotary evaporation, and flash column chromatography using polar
solution intervals of 10:90, 20:80, and 30:70 of CH2Cl2 (l) : heptane (l) is performed to acquire the final
epoxide solution. The solvent is then removed by rotary evaporation and the epoxide is confirmed by
1
H-NMR with CDCl3 (l) and (Eu(hfc)3 (s) in CDCl3 (l). Repeat procedure using 500 mg of styrene.

Results

In Table 1 below, data regarding the experimental yielding, specific rotation, % ee (percent
enantiomer excess), and enantiomer ratio (according to information found in Appendix C,E,F & G) of
each synthesized product in this experiment can seen:

Table 1: Experimental Yield Values of Synthesized Epoxides and Jacobsens Catalyst7

Chemical Name Styrene Oxide 1,2-Dihydronapthalene Jacobsens Catalyst


Oxide
Theoretical Yield (g) 0.5 0.5 1
Experimental Yield (g) ----- 0.076 0.833
Percent Yield (%) ----- 15.2 83.3
Exp. Specific Rotation 6.154 ----- -274
()
Lit. Specific Rotation () 34.0 ----- -315
Enantiomer Excess (%) 18.1 [major (R,R)] 80.8 [major (R,R)] 86.98 [major (R,R)]
Enantiomer Ratio 1 : 0.819 1 : 0.192 1: 0.136
[(R,R):(S,S)]

The following calculation demonstrates that determination of the experimental specific rotation
of the styrene oxide synthesized in the experiment, where () is the specific rotation:
% ( )
% = 100% => = = 6.154
100%
In Table 2, the calculated retention factors of the TLC confirmation of the 1,2-dihydronapthalene
epoxidation and the separation of the epoxide enantiomers by flash column chromatography as seen
illustrated in Appendix A can be seen below:
Table 2: TLC Retention Factors of 1,2-Dihydronapthalene Epoxidation and Flash Column
Chromatography Fractions

Spot Solute Distance (cm) Solvent Distance (cm) Retention Factor


Epoxidation (R) 3.6 4.3 0.837
Epoxidation (C) 3.8 4.3 0.884
Epoxidation (S) 3.8 4.3 0.884
Fraction #2 3.5 4.3 0.814
Fraction #3 2.9 4.3 0.674
Fraction #8 2.3 4.3 0.535
Fraction #12 2.0 4.3 0.465
Fraction #13 2.0 4.3 0.465
Fraction #14 2.0 4.3 0.465

In Appendix B, the experimental 1H-NMR spectrum of the synthesized 1,2-dihydronapthalene


oxide can be seen with the following peaks: 1.249 ppm (s, i = 0.194, J = 0, B-H), 1.553 ppm (s, i = 0.608,
J= 0, C-H), 7.454-7.486 ppm (q, i = 0.965, J =3, A-H). In Appendix C, the experimental 1H-NMR spectrum
of the Eu(hfc)3 chiral shift of the synthesized 1,2-dihydronapthalene oxide can be seen with the
following peaks: 0.443-0.870 ppm (m(5), i = 2.481, J = 3.322, G-H (R,R) {0.565 ppm}, L-H (S,S) {0.694
ppm}, K-H (R,R) {0.846 ppm}, J-H (S,S) {0.870 ppm}), 1.252-1.437 ppm (d, i = 1.532, J = 2, F-H (S,S) {1.252
ppm}, E-H (R,R) {1.437 ppm}), 1.982 ppm (s, i = 0.536, J = 0, D-H), 3.247 ppm (s, i = 0.127, J = 0, C-H),
5.654-5.728 ppm (d, i = 1.03, J = 2, M-H (R,R) {5.654 ppm}, P-H (S,S) {5.728 ppm}), 7.450-7.480 ppm (q, i
= 0.99, J =3, B-H), 7.817-7.847 ppm (q, i = 1, J = 3, A-H).

In Appendix D, the experimental 1H-NMR spectrum of the synthesized styrene oxide can be seen
with the following peaks: 1.853-1.956 ppm (t, i = 2.08, J = 2.585, F-H {1.853-1.9045 ppm}, E-H {1.9045-
1.956 ppm}), 3.291-3.321 ppm (t, i = 1.04, J = 2.585, D-H), 6.963-6.971 ppm (d, i = 0.926, J = 2, A-H),
7.250 ppm (s, i = 1.25, J = 0, B-H), 7.280-7.287 ppm (d, i = 0.932, J = 2, C-H). In Appendix E-F, the
experimental 1H-NMR spectrum of the Eu(hfc)3 chiral shift of the synthesized styrene oxide can be seen
with the following peaks: 2.779-2.805 ppm (dd, i = 0.168 {2.779-2.787 ppm}, i = 0.171 {2.797-2.805
ppm}, J = 4, J-H (S,S) {2.779-2.787 ppm}, G-H (R,R) {2.797-2.805 ppm}), 3.121-3.153 ppm (dd, i = 0.17
{3.121-3.134 ppm}, i = 0.164 {3.139-3.153 ppm}, J = 4, E-H (R,R) {3.121-3.134 ppm}, F-H (S,S) {3.139-
3.153 ppm }), 3.839-3.861 ppm (dd, i = 0.149 {3.839-3.848 ppm}, i = 0.144 {3.852-3.861 ppm}, J = 4, C-H
(R,R) {3.839-3.848 ppm}, D-H (S,S) {3.852-3.861 ppm}), 7.247-7.367 ppm (m(7:5), i = 0.817 {7.247-7.288
ppm}, i = 1 {7.302-7.367 ppm}, J = 4.585, B-H (S,S) {7.247-7.288 ppm}, A-H (R,R) {7.302-7.367 ppm}).

In Appendix G, the experimental 1H-NMR spectrum of the synthesized Jacobsens Catalyst can
be seen with the following peaks: 1.230-1.328 ppm (q, i = 50.3, J = 2, A-H), 1.407-1.489 ppm (t, i = 51.7, J
= 2.585, B-H), 1.710-1.743 ppm (d, i = 3.69, J = 2, C-H), 1.858-1.964 ppm (t, i = 13.2, J = 2.585, D-H {1.858
ppm}, E-H {1.920-1.964 ppm}), 5.293 ppm (s, i = 1.33, J = 0, F-H), 6.973-6.981 ppm (d, i = 5.17, J = 2, G-H),
7.251-7.298 ppm (t, i = 8.83, J = 2.585, J-H), 8.295 ppm (s, i = 5.49, J = 0, K-H).

Discussion

As seen in Table 1, the percent yield of the epoxidase 1,2-dihydronapthalene is lower than what
is expected for the styrene; this observation can be attributed to the reaction between the 1,2-
dihydronapthalene and the synthesized Jacobsens Catalyst is more hindered than the expected reaction
between the Jacobsens Catalyst. Due to this hindrance, part of the reactant portion of the alkene could
have possibly not been able to fully react with the atmospheric oxygen and the catalyst to form the
epoxide, thus causing the remaining reactant to be extracted from the epoxide product by its solubility
in dichloromethane. This can be further explained by the long amount of time (one week of constant
stirring at ambient temperature) that the epoxidation of 1,2-dihydronapthalene was allowed to be
performed, yet still not reaching the full extent of the reaction. The hindrance between the catalyst and
the alkene would cause this increase in time for the reaction to occur fully, which would lower the
probability of necessary collisions between each molecule for the epoxidation to occur. Styrene is less
hindered compared to 1,2-dihydronapthalene due to the absence of the secondary carbon ring;
although 1,2-dihydronapthalene has a higher electron density that styrene, there is not enough torsion
of the bonds within 1,2-dihydronapthalene to help increase the probability of collisions with the
catalyst.

In Table 1, it can be seen that there is a greater % ee value for the 1,2-dihydronapthalene oxide
than that of the styrene oxide. This can be attributed also to the hindrance of the 1,2-dihydronapthalene
in comparision to styrene in reacting with atmospheric oxygen and Jacobsens catalyst. With the
limitation of torsion and other associated movement, 1,2-dihydronapthalene could become more
specific or prone to a certain plane of attack by the Jacobsens catalyst than the freely spinning styrene;
thus, this would allow 1,2-dihydronapthalene to form more of one enantiomer [(R,R)} than another
[(S,S)] in reaction with the Jacobsens Catalyst. It can also be attributed the enantiomer L-Tartrate used
to synthesize Jacobsens Catalyst in the experiment since the enantioselectivity of the Jacobsens
Catalyst is dependent on the plane of attack against an alkene and the use of either L-(+)-Tartrate or L-(-
)-Tartrate. With this, it can be inferred that the major enantiomer of the 1,2-dihydronapthalene would
be (R,R) configuration based on the induction of the epoxidation with used of the L-(+)-Tartrate to
synthesize the Jacobsens Catalyst.

In Table 2, it can be seen that the fractions #2 and #3 had the highest retention factors, which
inferred that the most polar solute was present. Since the produced epoxides were polar in comparison
the TLC solvent used, it insinuated that fractions #2 and #3 were the only fractions that contained the
desired epoxide; however, with a lower percent yield of the 1,2-dihydronapthalene found in Table 1, it
could be determined that some of product could have been present in fractions 8-15 based on the
presence of travel of the solute in comparison to allow other fractions that had no presence of solute
travel. If this is correct, then all of the epoxide product was not obtained for the final yield, thus
decreasing the overall percent yield.

In Appendix A-G, there are presentations of NMR peaks that do not seem to be associated with
predicted products, thus causing assumptions that some of the reaction flasks may have become
contaminated during the experiment; this could have induced other chemical reactions to occur and
cause the absence of certain predicted NMR groups (such as the hydroxide groups on the Jacobsens
Catalyst) and the inclusion of unknown NMR spectral peaks. If there was an fluctuation in the pH of the
reaction mixture, then the shifting of the hydroxide ions on the produced catalyst in Appendix G would
have become highly active and more likely to dissolve back into the reaction mixture than stay bonded
to the Jacobsens Catalyst.
Acknowledgments

I would like to thank Angel Sanchez for his contribution to this experiment by the performance
of the styrene epoxidation of Jacobsens Catalyst he synthesized and using the NMR data obtained from
this experiment to make the necessary comparisons in enantioselectivity between 1,2-
dihydronapthalene oxide and styrene oxide in this report.

References

(1) Carruthers, W. Some Modern Methods of Organic Synthesis, 3rd ed, Cambridge University
Press, New York, NY, section 6.3: Oxidation of Carbon-Carbon Double Bonds.
(2) Zhang, W.; Loebacch; J.L; Wilson, S.R; Jacobsen, E.N. J. AM. Chem. Soc. 1990, 112, 2801- 2803,
and references cited therein.
(3) Jacobsen et. Al. J. Am. Chem. Soc. 1991, 113, 7063-7064.
(4) Larrow, J.L.; Jacobsen, E. N. ; Gao, Y.; Hong, Y.; Nie, X.; Zepp, c. M. J. Org. Chem. 1994, 59,
1939-1942, and references cited therein
(5) Brandes, B. D.; Jacobsen E.N. J. Org. Chem. 1994, 4378-4380.
(6) Jacobsen, E. N. Asymmetric catalytic Epoxidation of Unfunctionalized Olefins in
Catalytic Asymmetric Synthesis I. Ojima, Ed.; VCH: New York, 1993.
(7) (R)-Styrene Oxide (CAS Number : 20780-53-4 Product Number : S0516). TCI Chemicals.
http://www.tcichemicals.com/eshop/en/us/commodity/S0516/ (accessed Oct 2015)
Appendix A: Experimental TLC Plate Series Illustrations
Appendix B: Experimental NMR Spectrums of 1,2-Dihydronapthalene Epoxide
Appendix C: Experimental NMR Spectrums of 1,2-Dihydronapthalene Chiral Shift
Appendix D: Experimental NMR Spectrums of Styrene Epoxide
Appendix E: Experimental NMR Spectrum of Styrene Epoxide Chiral Shift
Appendix F: Magnified NMR Spectral Peaks of Styrene Epoxide Chiral Shift

(a)

(b)
(c)

(d)
Appendix G: Experimental NMR Spectrums of Synthesized (R,R)-Jacobsens Catalyst
Research Article Incorporation
In Tsutomu Katsukis Catalytic Asymmetric Oxidations Using Optically Active (Salen)
Manganese (III) Complexes as Catalyst, he demonstrates knowledge from the key Jacobsen
article for this experiment by the understanding that the Jacobsens catalyst is indeed an
optically active reagent and demonstrates how optical activity may take part in the
enantioselectivity of the Jacobsens Catalyst during epoxidation of un-functionalized olfeins and
other alkene reagents. Katsuki also focuses on how salen manganese complexes such as
Jacobsens catalyst has the ability to be a transport for atmospheric oxygen into the
epoxidation of alkenes and relates that optical activity of the Jacobsens catalyst the reactivity
of the complex with oxygen in how it creates very selective bonds and planes of attack on the
alkenes to produce specific enantiomer products.
Questions
(1) Would you expect the (S,S)-catalyst to give the same or a different enantiomer as the
(R,R)-catalyst for a give olefin? Why? What can you expect for the ees?

I would expect that the (S,S)-catalyst to give a different enantiomer that the
(R,R)-catalyst to a given olefin due to the resulting stereochemistry of the R
groups and the hydrogens in the alkyl bond. The orientation is dependent on
which side the atmosphere oxygen attacks the double bond of the alkene, and
the enantiomeric excess would be higher in purity for one enantiomer than the
other due to this hindrance and selectivity in the nucleophilic attack on the
alkene.
(2) Why is it important to be able to synthesize molecules enantioselectively?

It is important to be able to synthesize molecules enantioselectively due to the


fact that it helps eliminate the result of a racemic mixture, which allows purity of
an enantioselective product. With this purity, the performance of experiments
that require certain enantioselective materials can be done easier by the fact
that other enantiomers will not be present in the reaction that may cause
hindrance or further steps to perform.

(3) Draw the structure of the epoxide below that has the 1S, 2R configuration. Which
catalyst (R,R) or (S,S) would you use to make that enantiomer?
(S, S) catalyst would be used due to the hindrance that would come with
the stereo selectivity of the benzene and methyl groups on the molecule. The catalyst would have a
higher success in performing the reaction if attacking from the least electron dense plane of the
alkene, thus attacking on the side of the methyl group, which can only be achieved if the
catalyst is (S,S) configuration by formation with L-(-)-Tartrate.