Asymmetric Epoxidation of Dihydronaphthalene with a Synthesized Jacobsen's Catalyst

Abstract. 1,2 diaminocyclohexane was reacted with L-(+)-tartaric acid to yield (R, R)-1,2-diaminocyclohexane mono-(+)-tartrate salt. The tartrate salt was then reacted with potassium carbonate and 3,5-di-tert-butylsalicylaldehyde to yield (R, R)-N, N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine, which was then reacted with Mn(OAc)2*4H2O and LiCl to form Jacobsen's catalyst. The synthesized Jacobsen's catalyst was used to catalyze the epoxidation of dihydronaphthalene. The products of this reaction were isolated, and it was found that the product yielded 1,2-epoxydihydronaphthalene as well as naphthalene.


In 1990, professor E. N. Jacobsen reported that chiral manganese complexes had the ability to catalyze the asymmetric epoxidation of unfunctionalized alkenes, providing enantiomeric excesses that regularly reaching 90% and sometimes exceeding 98% . The chiral manganese complex Jacobsen utilized was [(R, R)-N, N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminato-(2-)]-manganese (III) chloride (Jacobsen's Catalyst).

(R, R) Jacobsen's Catalyst

Jacobsen's catalyst opens up short pathways to enantiomerically pure pharmacological and industrial products via the synthetically versatile epoxy function.

In this paper, a synthesis of Jacobsen's catalyst is performed (Scheme 1). The synthesized catalyst is then reacted with an unfunctional alkene (dihydronaphthalene) to form an epoxide that is highly enantiomerically enriched, as well as an oxidized byproduct.

Jacobsen's work is important because it presents both a reagent and a method to selectively guide an enantiomeric catalytic reaction of industrial and pharmacological importance. Very few reagents, let alone methods, are known to be able to perform such a function, which indicates the truly groundbreaking importance of Jacobsen's work.

Experimental Section

General Protocol. 99% L-(+)- Tartaric Acid, ethanol, dihydronaphthalene and glacial acetic acid were obtained from the Aldrich Chemical Company. 1,2 diaminocyclohexane (98% mix of cis/trans isomers) and heptane were obtained from the Acros Chemical Company. Dichloromethane and potassium carbonate were obtained from the EM Science division of EM Industries, Inc. Manganese acetate was obtained from the Matheson, Coleman and Bell Manufacturing Chemists. Lithium chloride was obtained form the JT Baker Chemical Co. Refluxes were carried out using a 100 V heating mantle (Glas-Col Apparatus Co. 100 mL, 90 V) and 130 V Variac (General Radio Company). Vacuum filtrations were performed using a Cole Parmer Instrument Co. Model 7049-00 aspirator pump with a Büchner funnel. For Thin Layer Chromatography (TLC) analysis, precoated Kodak chromatogram sheets (silica gel 13181 with fluorescent indicator) were used in an ethyl acetate/hexane (1:4) eluent. TLC's were visualized using a UVP Inc. Model UVG-11 Mineralight Lamp (Short-wave UV-254 nm, 15 V, 60 Hz, 0.16 A). Masses were taken on a Mettler AE 100. Rotary evaporations were performed on a Büchi Rotovapor-R. Melting points were determined using a Mel-Temp (Laboratory Devices, USA) equipped with a Fluke 51 digital thermometer (John Fluke Manufacturing Company, Inc.). Optical rotations ([a]D) were measured on a Dr. Steeg and Renter 6mbH, Engel/VTG 10 polarimeter. Solid IR's were run on a Bio-Rad (DigiLab Division) Model FTS-7 (KBr:Sample 10:1, Res. 8 cm-1, 16 scans standard method, 500cm-1 - 4000cm-1). Flash Chromatography was carried out in a 20 mm column with an eluant of ethyl acetate (25%) in hexane.

(R, R)-1,2 Diaminocyclohexane mono-(+)-tartrate salt. 99% L-(+)-Tartaric Acid (7.53g, 0.051mol) was added in one portion to a 150 mL beaker equipped with distilled H2O (25 mL) magnetic stir bar, and thermometer. Once the temperature had dropped to 17.8 °C, 1,2 diaminocyclohexane (11.89 g, 12.5 mL, 0.104 mol) was added with stirring in one portion. To the resultant amber solution was added glacial acetic acid (5.0 mL, 0.057 mol). The frothy orange product was cooled in an ice water bath for 30 minutes. The product was washed with 5 °C distilled H2O (5.0 mL) and ambient temperature methanol (5.0 mL) and isolated by vacuum filtration. 8.37 grams of an orange slush were obtained. The product was further purified by recrystallization of the salt from H2O (1:10 w/v, 84 mL of H2O) and again isolated by vacuum filtration, yielding an off-white crystalline product (1.2015g; 0.00415 mol; 8.9 % yield; mp=270.4-273.8 °C Lit. Value mp=273 °C )

(R, R)-N, N'-Bis (3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine. Distilled H2O (6.0 mL), (R, R)-1,2 diaminocyclohexane mono-(+)-tartrate salt (1.1087 g, 0.0042 mol) and K2CO3 granules (1.16 g, 0.0084 mol) were added to a 100 mL RB flask equipped with a magnetic stir bar. The mixture was stirred until complete dissolution occurred, and then ethanol (22 mL, 0.376 mol) was added. The solution was then brought to reflux, and then a solution of 3,5-di-tert-butylsalicylaldehyde (2.0g, 0.0037 mol) dissolved in ethanol (10 mL, 0.1713 mol) was added with a Pasteur pipette. The solution refluxed for 45 minutes. H2O (6.0 mL) was added to the yellow solution, and the mixture cooled in an ice bath for 30 minutes. The resultant yellow solid was collected by vacuum filtration and washed with ethanol (5 mL, 0.856 mol). The yellow solid was dissolved in CH2Cl2 (25 mL, 0.4 mol) and washed with H2O (2 x 5.0 mL) and saturated aqueous NaCl (5.0 mL) The organic layer was dried (Na2SO4) and then decanted into an RB flask. Methanol was removed in vacuo, yielding a yellow crystalline powder (1.56g; 0.00285 mol; 77 % yield; mp=202.9-205.4 °C, Lit. Value mp=205-207 °CIII; IR (KBr) 2800, 2100, 1631.7, 1506.7, 1173.5, 828, 545cm-1; [a]D20 =-314°, Lit. Value [a]D20 =-315°III)

[(R, R)-N, N'-Bis (3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminato (2-)]-manganese (III) Chloride. Absolute ethanol (25 mL, 0.429 mol) was added to (R, R)-N, N'-bis (3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine (1.01 g, 0.001788 mol) in a 50 mL RB equipped with a magnetic stirrer, mantle, claisen adapter and reflux condenser. The pale yellow mixture was brought to reflux, and MnO(OAc)2*4H2O (2.0 equivalents, 0.881 g, 0.0036 mol) was added. The orange mixture refluxed for 30 minutes, and then the reaction flask was equipped with a glass bleed tube allowing air to bubble through at a slow rate. The progress of the reaction was monitored by TLC until the starting material ((R, R)-N, N'-bis (3,5-di-tert-butylsalicylidene)-1,2 cyclohexane diamine)) faded from the TLC readings (Rf=0). At this point, the air was discontinued and granular LiCl (3 equivalents, 0.24 g, 0.0054 mol) was added to the caramel brown mixture. The mixture was refluxed for an additional 39 minutes, and the ethanol was removed in vacuo. The brown solid was redissolved in CH2Cl2 (25 mL), washed with H2O (2x 10 mL) and saturated aqueous NaCl (15 mL). The organic phase was dried (Na2SO4) and redissolved in heptane (30 mL, 0.205 mol). The CH2Cl2 was removed in vacuo, and the brown slurry was cooled in an ice bath for 57 minutes. The brown solid (0.22g; 0.000354 mol; 19% yield; mp=331.4 -333.6 °C, Lit. Value mp=324-326 °CIII) was collected by vacuum filtration, and left to air dry for 1 week.

1,2-Epoxydihydronaphthalene. 0.05 M Na2HPO4 (5 mL, 0.037g 2.5*10-4 mol) was added to household Clorox bleach (12.5 mL), and the resultant clear liquid was adjusted to pH 11.3 by adding 1M NaOH (1 drop). [(R, R)-N, N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminato (2-)]-manganese (III) chloride (0.2 g, 0.00031 mol) was added to a solution of 4-phenylpyridine N-oxide (0.13 g, 0.00076 mol) and dihydronaphthalene (0.51 g, 0.0038 mol) in CH2Cl2 (5 mL, 0.076 mol). The brown liquid was stirred vigorously for 2 hours. The progress of the reaction was monitored by TLC until the starting material (dihydronaphthalene, Rf=) faded from the TLC readings (Rf=0). Once the starting material was gone, the stir bar was removed and dichloromethane (50 mL, 0.76 mol) was added. The brown organic phase was separated, washed twice (NaCl aq) and dried (Na2SO4). The brown organic layer was then isolated by vacuum filtration, and then the dichloromethane was removed in vaccuo. The dark brown, oily solid (0.4 g; 0.0027 mol; 71% yield; IR (NEAT) 2964.0, 2857.1, 1747.0, 1373.0, 1239.0, 1048.7cm-1; GC Retention Times (minutes) 3.75 (70%, naphthalene), 6.75 (29%, 1,2-epoxydihydronaphthalene)) was stored for one week and then purified by flash chromatography.

Results and Discussion

Synthesis of (R, R) Jacobsen's Catalyst (Scheme 1). The first step in the synthesis of Jacobsen's catalyst was the selective crystallization of one of three stereoisomers present in 1,2-diaminocyclohexane. The yield from this reaction was 8.9% (Appendix 1). The reaction produced 1.2015 g of an off-white crystal (Product 1) with a melting point of 270.4-273.8 °C, which was identified as (R, R)-1,2-diaminocyclohexane mono-(+)-tartrate salt (Table 1).

Table 1. Selected Data Utilized in Identification of Product 1

Compound Product 1 (R, R)-1,2-diaminocyclohexane mono-(+)-tartrate saltIII

Physical Description Off-white crystals Off-white to beige crystalline solid

Melting Point (°C) 270.4-273.8 273

The percent yield was so low (8.9%) largely because of experimental error. An unknown amount of Product 1 was lost because it was not retrievable from the reaction flask, and a further unspecified amount was lost when a portion of the product recrystallized on the filter paper during a vacuum filtration. This recrystallization occurred because the funnel and filter flask were not heated properly. The second step of the Jacobsen synthesis involved the reaction of the isolated diamine salt (Product 1, (R, R)-1,2-diaminocyclohexane mono-(+)-tartrate salt) with an aldehyde (3,5-di-tert-butylsalicylaldehyde) to produce the organic backbone of the catalyst. The percent yield from this reaction was 77%. This reaction produced 1.56 g of an oily, yellow powder (Product 2) with a melting point of 202.9-205.4 °C and an optical rotation ([a]D20) of -314° that was identified as (R, R)-N, N'-Bis (3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine (Table 2).

Table 2. Selected Data Used in Identification of Product 2

Compound Product 2 (R, R)-N, N'-Bis (3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamineIII

Physical description

Oily, yellow powder Yellow powder

Melting Point (°C)

202.9-205.4 205-207

[a]D20 -314° -315°

Product was lost during transfers between containers and in the separatory funnel when the reaction material was washed. It is also possible that product was lost because the reaction was not allowed to reflux to completion and was cut short by fifteen minutes. The fourth and final step of the Jacobsen catalyst synthesis involved the insertion of the oxidizing metal (in the form of Mn(OAc)2*4 H2O followed by 2 equivalents of LiCl) into the organic backbone (Product 2) of the catalyst. The percent yield for this reaction was 19%. The reaction produced 0.22 g of a brown, oily solid (Product 3) with a melting point of 331-333.6 °C that was identified as Jacobsen's catalyst; [(R, R)-N, N'-Bis (3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminato (2-)]-manganese (III) Chloride (Table 3).

Table 3. Selected Data Used in Identification of Product 3

Compound Product 3 Jacobsen's Catalyst

Physical Description Brown, oily solid

Brown Solid

Melting Point (°C) 331.4-333.6 324-326

Again, product was lost because the reflux was cut short and not allowed to run to completion, causing loss of product. Additional product was either lost or unreacted when the air bleed tube was inserted, causing some product to splash out of the reaction flask. These experimental errors may very well have led to a high amount of impurities in Product 3, which would account for the difference between the experimental melting point and the literature value. The net percent yield for the synthesis of Jacobsen's catalyst was 1.9% (Appendix 1)

Asymmetric Epoxidation of Dihydronaphthalene. The synthesized Jacobsen's catalyst (Product 3) was used to run an enantiomerically guided epoxidation of an unfunctionalized alkene (dihydronaphthalene). The percent yield for this reaction was 71%. The reaction yielded a 0.4 g of a dark brown, oily solid (Product 4) that was purified by flash chromatography, analyzed by GC/MS and IR (NEAT) (Figure 1, Table 4).

Table 4. Selected IR Data for Identification of Epoxidaton of Dihydronaphthalene Products

Compound Product 4***Fig 1,2-epoxydihydronaphthalene Naphthalene

Prominent IR Peaks 2964.0 (C-H, alkane)

1747.0 (C=C, alkene)

1239.0 (C-O, ether)

1048.7 (C=C-H, alkene)

2970-2850 (C-H, alkane)

1750-1620 (C=C, alkene)

1300-1000 (C-O, ether)

1050-675 (C=C-H, alkene) 2970-2850 (C-H, alkane)

1750-1620 (C=C, alkene)

1050-675 (C=C-H, alkene)


Retention Times (min.) and Corresponding Mass Spec (m/z) 3.75 min.: (128)

6.75 min.: (146)

Structure, Physical Properties



Product 4 displays properties of both 1,2-epoxydihydronaphthalene and naphthalene. The peaks seen in the IR (NEAT) of product 4 at 2964.0, 1747, 1239, and 1048.7 cm-1 (FIG 1) could be interpreted to represent the presence of just 1,2-epoxydihydronaphthalene. The GC that was run on product 4; however, indicated that naphthalene was also present (FIG 2-4). This leads to the conclusion final product of this Jacobsen catalyzed epoxidation was a mixture of 1,2-epoxydihydronaphthalene (30%) and naphthalene (70%) (FIG 2-3, Scheme 2). The presence of an oxidized product (naphthalene) indicates that the solution in which the reaction took place was probably too basic. Such a situation could be corrected by either adding less Clorox or by adding NaOH that is less concentrated than 1M. It is also possible that not all of the epoxidized product was isolated, and that much of it remained stuck in the silica gel of the flash chromatography column. In order to remedy this situation, a solvent that is more polar than the 25% ethyl acetate in hexane that was used for the flash chromatography in this experiment.


The synthesized Jacobsen's catalyst did not guide this enantiomeric epoxidation as was hoped; however, both the reagent and mechanism showed that it is possible to produce a significant amount of an enantiomerically enriched epoxide. The problem with the reaction described above was not the reagent or the mechanism of the reaction, it was the conditions in which the reaction was carried out. In order for the Jacobsen catalyzed epoxidation to produce highly enamtiomerically enriched epoxides as was hoped, more care must be taken in the transferring and washing of products, and reactions must be allowed to run to completion. If this is successfully done, then the impurities that were present in the final product will be effectively minimized, and the results that were obtained by Dr. E. N. Jacobsen may be repeated.

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