Checked by Matthew F. Schlecht, Howard Drossman, and Clayton H. Heathcock.
1. Procedure
A
6-L Erlenmeyer flask which contains a
large magnetic stirring bar is charged with
294 g (2 mol) of L-glutamic acid (Note
1) and 2 L of distilled water. The suspension is stirred vigorously while solutions of
168 g (2.4 mol) of sodium nitrite in 1.2 L of water and
1.2 L of aqueous 2 N sulfuric acid are added simultaneously from
separatory funnels (Note
2). After the addition is complete (Note
3), the solution is stirred at room temperature for an additional 15 hr. The water is then removed by heating below 50°C under reduced pressure with a
rotary evaporator (Note
4). The resulting pasty solid is triturated with
500 mL of boiling acetone and the hot solution is filtered and set aside to cool. This operation is repeated four times (Note
5) and (Note
6). Removal of solvent with a rotary evaporator affords
312 g of crude
(+)-γ-butyrolactone-γ-carboxylic acid as a slightly yellow oil (Note
7) and (Note
8).
A
250-mL, round-bottomed flask is equipped with a magnetic stirring bar and charged with
100 g of the foregoing crude lactone acid (Note
9). The flask is fitted with a Claisen distillation apparatus and connected to a
vacuum pump (Note
10) and (Note
11). The flask is gradually heated with an
oil bath (160°C) until gas evolution ceases (Note
12). At this point the oil bath is removed and the black, viscous oil is distilled with the use of a flame (Note
13). The product,
58 g (
70%), is collected as a colorless oil at
146–154°C (0.03 mm). The distillate crystallizes in the
receiver, mp
66–68°C (Note
14) and (Note
15).
2. Notes
1. This material was purchased from the Aldrich Chemical Company Inc.,
[α]23D +29° (6
N HCl,
c 1).
2. The addition requires about 30 min. During addition the reaction mixture should warm to 30–35°C and smooth evolution of NO
2 and N
2 should occur. If the solutions of NaNO
2 and H
2SO
4 are added too rapidly, more gas appears to be generated and a reduction in yield occurs.
3. At this point the reaction mixture is clear and colorless. Residual brown gas usually remains in the flask.
4. If a
conventional aspirator pump is employed, concentration can require several days. The checkers employed a rotary evaporator that was evacuated to approximately 3 mm by a vacuum pump. Two traps, one cooled in an
ice–salt bath and the other in an
acetone–dry-ice bath, were inserted between the rotary evaporator and the vacuum pump. In this way, the reaction mixture can be concentrated to a paste in about 16–20 hr.
5. Repetitive extraction may also be performed in a flask heated with a
water bath to 65°C;
acetone is removed by decantation.
Ethyl acetate has also been used for the extraction.
2
6. The checkers found that a higher recovery is obtained if the pasty solid is vigorously agitated during trituration with five
750-mL portions of boiling acetone.
7. The crude yield reported is in excess of the theoretical yield (
260 g). The checkers obtained crude yields of
243–259 g, probably because water was more efficiently removed in the concentration step.
8. Although this material is sufficiently pure for some applications, it is advisable to purify it further before use. Distillation
2 and crystallization
3 have been described. The submitters recommend purification by the distillation procedure given. By direct crystallization of
101 g of crude lactone acid from
ether–petroleum ether, the checkers obtained
36.5 g (
35%) of material, mp
72–74°C.
9. If the distillation is carried out on a larger scale, the yield is lower.
10. The submitters recommend a short-path distillation apparatus with large sections (i.e., wide bore) since the distillate partially crystallizes in the condenser during the distillation. It is important that the distillation apparatus have a Claisen head because the viscous material tends to bump.
11. The vacuum pump should be protected by a
soda–lime trap.
12. During this heating period the system pressure should rise from 0.03 to 0.5 mm and the crude lactone acid should become black. When gas evolution ceases, the pressure decreases to its initial value.
13. Distillation should be carried out briskly. If a simple
bunsen burner with a low flame is used, distillation requires several hours. The checkers used a hot flame, about 13 cm in length, from a gas–air torch. In this way, the distillation requires only about 15 min. Distillation is discontinued when colored vapors appear.
14. The checkers distilled crude lactone acid obtained in approximately quantitative yield (
259 g). When this material was used, distillation of 100-g portions gave
64.3–66.4 g (
65–66% yield).
15. The submitters report that recrystallization from
ethyl acetate–petroleum ether raises the melting point to 73°C. The product obtained is analytically pure,
[α]21D + 16° (EtOH,
c 2). When the checkers used
ethyl acetate–
petroleum ether they often obtained an oily product.
The spectrum of the lactone acid is as follows: 1H NMR (CD3COCD3) δ: 2.1–2.9 (m, 4 H), 4.85–5.15 (m, 1 H), 5.1 (s, 1 H, COOH).
3. Discussion
The
(S)-(+)-γ-butyrolactone-γ-carboxylic acid is a useful intermediate for the synthesis of pheromones,
4 natural lignans,
5 and other derivatives.
6 In the same manner, but starting with
D-glutamic acid, the (
R)-(−)-lactone acid may be prepared.
7 Lactonization occurs with full retention of configuration at the chiral center.
8,9 Recently, authors have described an efficient method that allows the formation of derivatives of the (
R)-(−)-lactone from the more available (
S)-(+) counterpart.
10
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