Organic Syntheses, CV 6, 101
[Benzene, (chloromethyoxy)methyl-]
Submitted by D. S. Connor
1,2, G. W. Klein
13, G. N. Taylor
14, R. K. Boeckman, Jr.
5, and J. B. Medwid
6.
Checked by E. M. Carreira, S. E. Denmark, and Robert M. Coates.
1. Procedure
Caution!
Benzyl chloromethyl ether is a powerful alkylating agent and a potential carcinogen. Furthermore, it is a mild lachrymator and reacts with water and alcohols, forming
hydrogen chloride. The procedure should be conducted in a
hood, and inhalation and skin contact should be avoided.
A
1-l, three-necked flask equipped with an overhead
mechanical stirrer with a
Teflon paddle,
gas-inlet tube,
thermometer, and a
calcium chloride drying tube (Note
1) is charged with
216 g. (2.00 moles) of benzyl alcohol (Note
2) and
66 g. (2.20 moles as CH2O) of paraformaldehyde (Note
3). The resulting mixture is maintained at 20–25° with a
water bath during addition of anhydrous
hydrogen chloride (Note
4) at a moderate rate, with stirring (Note
5). After approximately 2 hours the reaction is complete, as judged by the appearance of two clear homogeneous phases (Note
6). The layers are separated, and the upper layer is diluted with
800 ml. of pentane and dried over anhydrous
magnesium sulfate for 3 hours at 0°, with stirring. The drying agent is removed by filtration,
2–3 g. of anhydrous calcium chloride is added to the filtrate, and the solution is concentrated on a
rotary evaporator (Note
7). The residual liquid, which is nearly pure
benzyl chloromethyl ether, is decanted, affording
260 g. (
83%) of crude product (Note
8). This crude
benzyl chloromethyl ether, which is suitable for use in some applications, is stored over anhydrous
calcium chloride at 0° under an inert atmosphere (Note
9) and (Note
10).
If further purification is desired, just prior to use the crude material (40 g.) may be distilled at approximately 3 mm from anhydrous
calcium chloride (Note
11), affording very pure
benzyl chloromethyl ether (
35 g.), b.p.
70–71° (3 mm.) (Note
12) and (Note
13).
2. Notes
1. A
Claisen adapter is utilized to accommodate both the thermometer and calcium chloride drying tube.
2.
Fisher Scientific reagent grade benzyl alcohol was freshly distilled prior to use.
5. The gas-inlet tube utilized was a Pasteur pipet; however, a
fritted glass gas-dispersion tube could be utilized.
Hydrogen chloride is introduced as a stream of fine bubbles; the rate of addition controls the reaction temperature.
6. To judge whether the reaction is complete, stirring is stopped and the phases are permitted to separate.
1H NMR analysis of the upper phase (CDCl
3) showed that the reaction is complete and devoid of major side-products.
7. Decomposition was noted during concentration and distillation in the absence of anhydrous
calcium chloride.
8. The checkers obtained
316.3–316.6 g. (
101%).
9. The crude material is satisfactory for the
C-alkylation of an ester enolate; little difference was noted when the crude material was substituted for distilled material.
10. The crude product exhibits singlets in the
1H NMR (CCl
4) at δ 4.68 (2H), 5.41 (2H), and 7.29 (5H). Both
1H NMR and GC analyses indicate a purity of greater than 90%. GC analysis was carried out at 155° with a
2 m. × 0.7 cm. column packed with silicone fluid No. 710 suspended on 60–80 mesh finebrick. The major impurities appear to be varying amounts of
benzyl chloride and
dibenzyl formal, by
1H NMR analysis.
11. Complete decomposition occurs if distillation is attempted at atmospheric pressure. Minor to occasionally major decomposition occurs upon attempted distillation at reduced pressure in the absence of anhydrous
calcium chloride, which retards the decomposition significantly.
12. The product gave satisfactory microanalytical data after one distillation. The reported physical constants for
benzyl chloromethyl ether are b.p.
96–98° (9.5 mm.),
7 n20D 1.5264–1.5292.
8,9
13. The checkers used a procedure identical to that described above at one-eighth scale to prepare
bromomethyl ether, using
hydrogen bromide. A quantitative yield of crude material was obtained and distilled, giving a
97% yield of pure
benzyl bromomethyl ether, b.p.
55–57° (1 mm.),
n20D 1.5547:
1H NMR (CDCl
3): δ 4.67 (s, 2H), 5.66 (s, 2H), 7.30 (s, 5H). Analysis calculated for C
8H
9BrO (201.09): C, 47.79; H, 4.51; Br, 39.74. Found: C, 48.05; H, 4.68; Br, 40.05. This was found to be a superior alkylating agent.
3. Discussion
Benzyl chloromethyl ether is useful for introduction of a potential hydroxymethyl group in alkylation reactions. Hill and Keach
10 first used this method and found it convenient in barbiturate syntheses. Graham and McQuillin,
11 and Graham, McQuillin, and Simpson
12 have extended the scope of the alkylation reaction to various ketone derivatives. They also have investigated the conditions for obtaining maximum
C-alkylation and the stereochemistry of alkylation in various octalone systems.
11 Alkylation of ketones followed by
sodium borohydride reduction and catalytic hydrogenolysis represents a convenient method for obtaining 1,3-diols.
11 Similarly, Wolff-Kishner reduction and catalytic hydrogenolysis give primary alcohols.
11 A procedure of this type has been used for obtaining bridgehead methanol derivatives of bicyclic compounds.
13 Alkylation of ester enolates, generated by
lithium diisopropylamide, has been reported.
14
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