Checked by Nakcheol Jeong and Martin F. Semmelhack.
1. Procedure
Caution! The ozonolysis reaction produces peroxidic intermediates that can present a potential explosion hazard. Accordingly, it is recommended that the following experiments be carried out in a hood and behind a safety shield.
A. A
500 mL, three-necked, round-bottomed flask is fitted with a
glass tube to admit ozone, a
calcium chloride drying tube, a
glass stopper, and a
magnetic stirring bar and is charged with
6.161 g of cyclohexene (0.075 mol),
250 mL of dichloromethane, and
50 mL of methanol (Note
1). The flask is cooled to ca. −78°C (2-propanol–dry ice), and
ozone (Note
2) is bubbled through the solution with stirring. When the solution turns blue,
ozone addition is stopped.
Nitrogen is passed through the solution until the blue color is discharged (Note
3) and then the cold bath is removed. The drying tube and
ozone inlet are replaced with a
stopper and rubber septum, and
1.215 g of p-toluenesulfonic acid (TsOH) (10% w/w) (Note
4) is added. The solution is allowed to warm to room temperature as it stirs under an atmosphere of
nitrogen for 90 min. Anhydrous
sodium bicarbonate (2.147 g, 4 mol-equiv) is added to the flask and the mixture is stirred for 15 min, and then
12 mL of dimethyl sulfide (0.150 mol) (Note
5) is added. After being stirred for 12 hr, the heterogeneous mixture is concentrated to approximately 50 mL by rotary evaporation.
Dichloromethane (100 mL) is added and the mixture is washed with 75 mL of water (Note
6). The aqueous layer is extracted with two more
100-mL portions of dichloromethane, and the combined organic layers are washed with 100 mL of water. After extracting the aqueous layer with
100 mL of dichloromethane, the organic layers are dried over anhydrous
magnesium sulfate, filtered, and concentrated by rotary evaporation. Short-path distillation of the crude product (Note
7) gives
8.2–8.4 g of
6,6-dimethoxyhexanal,
68–70%, bp
80–82°C/1.75 mm (Note
8) and (Note
9).
B. A round-bottomed flask equipped as in Step A is charged with
6.161 g of cyclohexene (0.075 mol),
250 mL of dichloromethane,
50 mL of methanol, and
2.0 g of anhydrous sodium bicarbonate (Note
1) and (Note
10). After the apparatus is cooled to ca. −78°C.
ozone (Note
2) is bubbled through the solution as it is stirred.
Ozone addition is stopped when the solution turns blue.
Nitrogen is passed through the solution until the blue color is discharged (Note
3) and then the cold bath is removed. The solution is filtered into a
l-L, round-bottomed flask and
80 mL of benzene is added. The volume is reduced to approximately 50 mL by rotary evaporation (Note
11). After dilution with
225 mL of dichloromethane the flask is cooled to 0°C and
16 mL of triethylamine (0.113 mol) and
21.24 mL of acetic anhydride (0.225 mol) are added via
syringe (Note
12), and the solution is stirred under a
nitrogen atmosphere for 15 min. The
ice bath is removed and stirring is continued for 4 hr. The solution is washed with
150-mL portions of aqueous 0.1 N hydrochloric acid, aqueous
10% sodium hydroxide, and water. The organic layer is dried over anhydrous
magnesium sulfate and filtered, and the solvent is removed by rotary evaporation. Short-path distillation of the crude product yields
methyl 6-oxohexanoate, (
7.0–7.8 g,
65–72%), bp
83–86°C/1.5 mm (Note
13).
C.
Cyclohexene, 6.161 g (0.075 mol), is stirred with
ozone in
dichloromethane and
methanol, as above. The resulting solution is treated with
p-toluenesulfonic acid and subsequently neutralized with
sodium bicarbonate, as described in Procedure A. The solution is filtered into a 1-L, round-bottomed flask,
80 mL of benzene is added, and the volume is reduced to approximately 50 mL by rotary evaporation (Note
11). Dilution with
dichloromethane, treatment with
triethylamine and
acetic anhydride, and workup as described in Procedure B followed by short-path distillation provides
methyl (6,6-dimethoxy)hexanoate, (
11.2–11.8 g,
78–83%), bp
87–91°C/1.5 mm (Note
14).
2. Notes
2.
Ozone was produced by a Welsbach Corporation Ozonator, style T-709, with the voltages set at 100 V and
oxygen pressure at 7 psi to give approximately
2% ozone concentration. The input
oxygen was passed through a
column of Hammond Drierite to ensure dryness.
3. The blue color indicates that cleavage of the olefin is complete. Excess
ozone is removed to prevent overoxidation
4. Although the ozonolysis product exists in oligomeric form, the amount of acid used was calculated by assuming a theoretical yield of the corresponding monomeric aldehyde–methoxy hydroperoxide.
p-Toluenesulfonic acid monohydrate, purchased from Aldrich Chemical Company, Inc., was not purified further.
5. The solution is neutralized to prevent bisacetal formation on subsequent reduction.
Dimethyl sulfide was purchased from Aldrich Chemical Company, Inc. and used without purification.
6. An aqueous workup facilitates the removal of
dimethyl sulfoxide produced by the reduction of the peroxide.
7. Typically
12.4–13.0 g of crude product is obtained after solvent removal. Material of this quality is satisfactory for most subsequent reactions.
8. The distilled product is similar in purity to the crude material. A small amount of
dimethyl sulfoxide and minor impurities remain. Purification of the crude product by flash chromatography (1:1 ether:hexanes) affords
6,6-dimethoxyhexanal that is pure by
1H and
13C NMR in
90–95% yield.
9. The following spectral properties of the product were observed:
1H NMR (CDCl
3), δ: 1.4–1.7 (m, 6 H), 2.4 (t, 2 H,
J = 7), 3.3 (s, 6 H), 4.3 (t, 1 H,
J = 5.3), 9.7 (t, 1 H,
J = 2.5).
13C NMR (CDCl
3), δ: 21.4, 23.7, 31.8, 43.2, 52.1, 103.9, 201.6. IR (film), cm
−1: 2700, 1720, 1100. MS,
m/e (rel. %): 113(95), 57(100).
11.
Benzene is added to facilitate the removal of
methanol. Although an aqueous wash will remove the
methanol, azeotropic removal with
benzene is simpler and provides a slightly higher yield.
13. The following spectral properties were observed:
1H NMR (CDCl
3), δ: 1.5–1.7 (m, 4 H), 2.2–2.4 (m, 4 H), 3.6 (s, 3 H), 9.7 (t, 1 H,
J = 2.5).
13C NMR (CDCl
3), δ: 21.1, 24.0, 33.2, 42.9, 51.0, 173.1, 201.4. IR (film), cm
−1: 2700, 1720, 1150. MS:
m/e (rel. %): 159(1), 29(3), 75(100).
14. The following spectral properties were observed:
1H NMR (CDCl
3), δ: 1.0–1.6 (m, 6 H), 2.15 (t, 2 H,
J = 8), 3.2 (s, 6 H), 3.6 (s, 3 H), 4.25 (t, 1 H,
J = 5.5).
13C NMR (CDCl
3), δ: 23.7, 24.3, 31.8, 33.4, 50.7, 52.0, 103.9, 173.1. IR (film), cm
−1: 1735, 1050, MS:
m/e (rel. %): 159(10), 127(30), 75(100).
3. Discussion
The ozonolytic cleavage of cycloalkenes in the presence of
methanol produces a chain with an aldehyde and a methoxy hydroperoxide group at the termini.
8 The unsymmetrical ozonolysis product is manipulated in several ways. Dehydration of the methoxy hydroperoxide group affords an ester (Step B). Alternatively, the aldehyde moiety is protected as an
acetal. Under these conditions, the methoxy hydroperoxide is reduced
9 (Procedure A) or dehydrated (Step C).
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
p-toluenesulfonic acid (TsOH)
ACETAL (105-57-7)
hydrochloric acid (7647-01-0)
Benzene (71-43-2)
methanol (67-56-1)
acetic anhydride (108-24-7)
sodium hydroxide (1310-73-2)
sodium bicarbonate (144-55-8)
magnesium (7439-95-4)
Adipic acid (124-04-9)
Cyclohexene (110-83-8)
oxygen (7782-44-7)
nitrogen (7727-37-9)
dichloromethane (75-09-2)
ozone (10028-15-6)
magnesium sulfate (7487-88-9)
Cyclopentene (142-29-0)
dimethyl sulfide (75-18-3)
dimethyl sulfoxide (67-68-5)
triethylamine (121-44-8)
calcium hydride (7789-78-8)
2-hydroxycyclohexanone
p-toluenesulfonic acid (104-15-4)
trimethyl orthoformate (149-73-5)
Methyl 6-oxohexanoate,
Hexanoic acid, 6-oxo-, methyl ester (6654-36-0)
6,6-Dimethoxyhexanal,
hexanal, 6,6-dimethoxy- (55489-11-7)
hexanoic acid, 6,6-dimethoxy-, methyl ester,
methyl (6,6-dimethoxy)hexanoate,
Methyl 6,6-dimethoxyhexanoate (25176-55-0)
ε-caprolactone (502-44-3)
cyclohexanone enol acetate
phosphorus pentoxide (1314-56-3)
p-toluenesulfonic acid monohydrate (6192-52-5)
lead tetraacetate
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