Checked by Paul F. Sherwin and Robert M. Coates.
1. Procedure
A.
1,2,4,5-Hexatetraene in ether solution. A
2-L, four-necked, round-bottomed flask is equipped with a mechanical stirrer, a reflux condenser fitted with a drying tube containing anhydrous calcium sulfate (Drierite), a dropping funnel, and a thermometer (Note
1). The flask is charged with
0.5 g (0.002 mol) of mercury(II) chloride and
29.2 g (1.2 mol) of magnesium turnings that have been crushed with a
mortar and pestle, and the apparatus is flushed with
nitrogen while being heated externally with a
Bunsen burner to remove traces of moisture. In the cooled flask are placed
160 mL of anhydrous ethyl ether (Note
2) and
7.6 g (5.0 mL, 0.064 mol) of propargyl bromide (Note
3). The
ether begins to reflux within 1 min, indicating that formation of the Grignard reagent has begun (Note
4). The mixture is cooled to 5° in an
ice-salt bath and stirred vigorously as a solution of
135 g (89 mL, 1.13 mol) of propargyl bromide in
560 mL of anhydrous ether is added. The addition rate is adjusted so as to maintain the internal temperature between 5°C and 10°C (Note
5). The cooling bath is removed, and the dark green mixture is stirred for 45 min at room temperature (Note
6). A
2-g (0.02 mol) portion of finely pulverized, dry copper(I) chloride (Note
7) is added, and the mixture, which becomes a chocolate-brown color after 2–3 min, is stirred for 15 min at room temperature and cooled again to 5°C with either an
ice-water bath or an
ice-salt bath. Stirring is continued while a solution of
128 g (85 mL, 1.08 mol) of propargyl bromide in
100 mL of ether is added at a rate such that the internal temperature is kept at ca. 20°C (Note
8). The mixture becomes almost black, and two phases are discernible when the stirrer is stopped, especially toward the end of the addition. The cooling bath is removed and stirring is continued for 15 min at room temperature to complete the dimerization. The reaction mixture is cooled to 0°C with an
ice-salt bath and stirred vigorously as
200 mL of 1 N aqueous hydrochloric acid is added (Note
9). The two-phase mixture is warmed to room temperature, and another
100 mL of 1 N hydrochloric acid is added. The
ether layer is separated and washed with three 100-mL portions of water (Note
10). A few crystals
(0.2–0.5 g) of hydroquinone are added to stabilize the reddish solution, which is then dried with anhydrous
potassium carbonate. The drying agent is filtered, and the filtrate is concentrated to a volume of ca. 400 mL by distillation under
nitrogen at atmospheric pressure with a
40-cm Vigreux column and a
heating bath kept at 40–45°C. The concentrate is purified by vacuum transfer (Note
11), and the now colorless solution, which contains ca.
25–30 g (
30–36%) of
1,2,4,5-hexatetraene, is stabilized by adding another 0.1–0.5 g of
hydroquinone (Note
12) and (Note
13).
B.
Tetramethyl[2.2]paracyclophane-4,5,12,13-tetracarboxylate. The 1-L flask from Step A containing ca.
25–30 g (0.32–0.38 mol) of 1,2,4,5-hexatetraene in
ether solution is equipped with a magnetic stirring bar and a 40-cm Vigreux column for distillation at atmospheric pressure. A solution of
69.4 g (60 mL, 0.49 mol) of dimethyl acetylenedicarboxylate (Note
14) in
220 mL of benzene (Note
15) is added. The resulting solution is stirred and heated at 45°C for 5–7 hr and at 70°C for 20 hr (Note
16). The
ether distils slowly at 45°C and rather rapidly at 70°C, the color of the solution changes from yellow to red–orange, and a white solid is gradually deposited. The mixture is cooled and filtered. Recrystallization of the solid from
600–800 mL of toluene affords
27–35 g of white crystalline product, mp
201.5–203°C. The original
benzene filtrate and the
toluene mother liquor, when evaporated to dryness and crystallized separately from
40–70 mL of toluene, provide 3–4 g and 2–3 g of product, respectively, having essentially the same melting point. The combined yield is
33–41 g (
40–50% based on
1,2,4,5-hexatetraene) (Note
17) and (Note
18).
2. Notes
1. The checkers used a
three-necked flask equipped with a Claisen adapter. The straight branch of the adapter was fitted with a thermometer, and the curved branch was mounted with a condenser bearing a nitrogen inlet. After the nitrogen-filled apparatus had been flamed dry and cooled, the dropping funnel was capped with a rubber septum. A
nitrogen atmosphere was maintained in the apparatus at all times, and liquids were placed in the dropping funnel via syringe.
2. The checkers dried the
ether by distillation from
sodium benzophenone ketyl immediately before use.
3.
Propargyl bromide may be purchased from Fluka. The reagent may also be prepared by the procedure of Gaudemar.
2 Propargyl bromide (97%) supplied by Tridom Chemical Inc. was dried by the checkers prior to use by stirring over Linde-type 4A molecular sieves under a
nitrogen atmosphere for 2–3 days. The volumetric quantities given in the procedure are for
97% propargyl bromide, which has a density of 1.56 at 20°C according to a catalog from Tridom Chemical Inc.
4. The submitters initiated Grignard formation by adding a few milliliters of a solution of
142.8 g (1.2 mol) of propargyl bromide in
560 mL of anhydrous ether. If the reaction does not begin, they suggest that the flask be heated with a warm stream of air from a "heat gun."
5. The checkers found that the addition time varied from ca. 1 to 4 hr, depending on the temperature of the cooling bath and the extent to which it was stirred.
7. The submitters used
copper(I) chloride purchased from E. Merck, Darmstadt, which had a greenish tinge attributed to slight contamination by copper(II) salts. The reagent used by the checkers was supplied by J. T. Baker Chemical Company.
8. The checkers, using an
ice-salt cooling bath, maintained the internal temperature between 7°C and 12°C. The addition time varied from 15 to 75 min depending on the efficiency of the cooling.
9. The internal temperature was maintained at 10–15°C by the submitters and 5–12°C by the checkers. The time required for the hydrolysis was reduced by the checkers by prior chilling of the
hydrochloric acid.
10. Since the product is unstable to
oxygen, the checkers tried to keep the ethereal solution under a
nitrogen atmosphere during transfer and extractions.
11. The crude solution of
1,2,4,5-hexatetraene may also be employed in part B. However, yields are lower, and the purification of the product becomes tedious owing to the presence of insoluble by-products. The vacuum transfer may be accomplished with a simple distillation apparatus equipped with a magnetic stirring bar and a
1-L, round-bottomed flask as receiver in the following manner. The crude ethereal solution is chilled to a glass with a
liquid nitrogen bath, and the apparatus is evacuated to a pressure of 1–3 mm with a vacuum pump. The apparatus is isolated from the vacuum pump, the cooling bath is removed, and the
ether glass is allowed to warm until it becomes mobile. The freeze–evacuate–thaw cycle is repeated two more times to complete the degassing process. The solution is again chilled with liquid
nitrogen, the apparatus is evacuated to 1–3 mm, and the system is then isolated from the vacuum pump. The receiving flask is cooled with a liquid
nitrogen or
dry ice-isopropyl alcohol bath, the cooling bath is removed from the distilling flask, and the
ether solution is stirred and allowed to warm to room temperature in the closed system. Once the
ether solution becomes mobile, the flask may be warmed cautiously with a
water bath at room temperature to speed up the vacuum transfer.
12. Pure
1,2,4,5-hexatetraene polymerizes readily when exposed to air at room temperature. However, solutions of the purified compound are stable for months at 0°C, especially if protected by an inert gas. Contact with air should be minimized to avoid inducing polymerization.
13. The amount of
1,2,4,5-hexatetraene in solution was estimated by the submitters from
1H NMR spectra and GC analyses. The major product of the dimerization reaction is
1,2-hexadien-5-yne. The submitters have shown that this hydrocarbon does not interfere with the cycloaddition in Step B.
14.
Dimethyl acetylenedicarboxylate is supplied by Aldrich Chemical Company, Inc.; E. Merck, Darmstadt; and Fluka. The reagent, bp
110–112°C (15 mm), was distilled before use.
15. The checkers carried out one run on one-tenth scale using
toluene instead of
benzene in part B. The yield of
tetramethyl[2.2]paracyclophane-4,5,12,13-tetracarboxylate, mp
202.5–204°C, was
2.91 g (
35% based on
1,2,4,5-hexatetraene in part A).
16. The conditions and isolation procedure given are those used by the checkers. The submitters heated the solution first to 45°C, after which the temperature was gradually increased to 70°C over several hours. The solution was then heated at 70°C overnight, and the solvents were removed by rotary evaporation. The semisolid, yellow-orange residue was recrystallized from
benzene or
methanol. Concentration of the mother liquor afforded additional crops of crystalline product. The total yield of the tetraester was
25–30 g (
30–36% based on
1,2,4,5-hexatetraene), mp
206–207°C.
17. The melting point of the product obtained by the checkers increased only slightly to
202–203.5°C on recrystallization from
toluene,
benzene, or
methanol. The once-recrystallized product was analyzed by the checkers. Anal. calcd. for C
24H
24O
8: C, 65.45; H, 5.49. Found: C, 65.51; H, 5.49. The submitters obtained material of analytical purity by sublimation at 180°C (0.001 mm).
The spectral properties of the product are as follows: IR (potassium bromide) cm
−1: 1715, 1260, 1195, 1125, 1005, 870;
1H NMR (CDCl
3) δ: 2.93–3.43 (nine-line
AA'BB' multiplet, 8, two C
H2C
H2), 3.83 (singlet, 12, four CO
2C
H3), 6.80 (singlet, 4, four aryl C
H); proton-decoupled
13C NMR (CDCl
3) δ (assignment): 33.27 (
CH
2), 52.25 (O
CH
3), 131.51 (
CCO
2CH
3), 134.98 (
CCH
2), 139.68 (
CH), 168.40 (
CO
2CH
3).
TABLE I
[2.2]PARACYCLOPHANES PREPARED BY DIELS-ALDER REACTION OF DISUBSTITUTED ACETYLENES WITH 1,2,4,5-HEXATETRAENE3, 4
|
|
R |
mp (°C) |
Yield (%) |
|
|
CO2CH3 |
203 |
47 |
CO2C2H5 |
133.5 |
30 |
CO2C(CH3)3 |
205 |
20 |
CO2H |
365 (dec) |
5 |
CN |
320 (dec) |
37 |
CF3 |
174 |
21 |
|
18. The submitters have scaled up this procedure to prepare as much as 60 g of the paracyclophane in one run. However, since the volumes of solvents and flasks are quite large, the operations become rather cumbersome.
3. Discussion
The principal methods used previously for the preparation of [2.2]paracyclophanes have been reviewed several times
5,6,7,8,9,10,11,12,13 and include (1) intramolecular Wurtz coupling of appropriately substituted dihalides at high dilution; (2) ring contraction of cyclophanes having larger bridges by
sulfone pyrolysis (the most versatile procedure currently known), Stevens rearrangement, and other extrusion reactions; and (3) the dimerization of transient
p-quinodimethane intermediates (
p-xylylenes), usually generated from
p-xylene precursors by elimination reactions.
18 A
p-quinodimethane is presumably also formed initially in Step B of this procedure. This cycloaddition route to
p-quinodimethanes and [2.2]paracyclophanes, discovered for the first time in the submitters' laboratories, is attractive on account of the availability of the starting materials, the simplicity of the procedure, and the relatively large quantities of product that may be obtained. The approach appears to be fairly general, since both the bisallene and acetylene components may be varied (Table I).
19,3,4 However,
methyl 2-butynoate,
2-butyne,
diphenylacetylene, and
bistrimethylsilylacetylene failed to react with
1,2,4,5-hexatetraene. Another limitation is the exclusive formation of [2.2]paracyclophanes with the
anti configuration from disubstituted acetylenic dienophiles.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
sodium benzophenone ketyl
TETRAMETHYL[2.2]PARACYCLOPHANE-4,5,12,13-TETRACARBOXYLATE
chromium tricarbonyl complexes
potassium carbonate (584-08-7)
hydrochloric acid (7647-01-0)
Benzene (71-43-2)
methanol (67-56-1)
ether,
ethyl ether (60-29-7)
hydroquinone (123-31-9)
magnesium turnings (7439-95-4)
sulfone (7446-09-5)
oxygen (7782-44-7)
nitrogen (7727-37-9)
toluene (108-88-3)
mercury(II) chloride (7487-94-7)
copper(I) chloride (7758-89-6)
Diphenylacetylene (501-65-5)
1-propynylmagnesium bromide
Dimethyl acetylenedicarboxylate (762-42-5)
2-butyne (503-17-3)
propargyl bromide (106-96-7)
1,2,4,5-Hexatetraene (29776-96-3)
allenylmagnesium bromide
1,2-hexadien-5-yne (33142-15-3)
methyl 2-butynoate (23326-27-4)
bistrimethylsilylacetylene (14630-40-1)
p-quinodimethane
Tricyclo[8.2.2.24,7]hexadeca-4,6,10,12,13,15-hexaene-5,6,11,12-tetracarboxylic acid, tetramethyl ester
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