AZIDES

32 AZIDES

1. INTRODUCTION A. Hazards and Safe Handling Practices B. Methods 32-1. Preparation of w-Butyl Azide 32-2. Preparation of Phenyl Azide 32-3. Preparation of Cross-Linked Poly(acrylazide)

1. INTRODUCTION

Τ

X he most generally useful method of preparing azide and acyl azides makes use of the displacement of other functional groups by azide ions (Eq. 1). RX + N a N 3

> R N 3 + NaX

(1)

X = halide, acyl halide, sulfonyl halide, bridgehead hydroxyl, etc.

Other useful preparations involve diazo transfer reactions. In the aromatic series diazonium salts may be reacted with sodium azides (Eq. 2). ArN 2X" Ä

ArN 3

(2)

From S. R. Sandler and W. Karo, Organic Functional Group Preparations, Vol. II, 2d ed. (Orlando, Florida, 1986), 323ff., by permission of Academic Press, Inc. 237

238

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Hydrazine derivatives may be treated with nitrous acid to form azides, a reaction which is of particular value in preparing polymeric acrylazide. Hydrazoic acid may be added to activated olefinic bonds to yield azides. Some epoxy compounds have also been reacted with sodium azide to form hydroxy azides. A. H A Z A R D S A N D S A F E H A N D L I N G

PRACTICES

• CAUTION: Although organic azides are reputed to be explosive materials, detailed information on hazards and safety precautions is sparse. Smith called acetyl azide "treacherous" [1]. The explosive hazard may be a function of the size of the molecule. For example, methyl azide is reported to be handled in a routine manner (but not in the presence of mercury) [1]. Yet, while this chapter was in preparation, Burns and Smith reported an explosion during the preparation of this very compound from dimethyl sulfate and sodium azide while sodium hydroxide was being added [2]. They attributed the explosion to the formation of hydrazoic acid during the preparation, when the pH of the reaction mixture may have dropped below 7. They therefore recommend adding the indicator bromthymol blue to the reaction mixture. This indicator changes color from deep blue at pH 6.5 to yellow at pH 8. The rate of base addition can then be monitored readily by observing the color of the reaction mixture and maintaining the pH at 8 or higher, throughout the reaction. Since the indicator may fade during the process, additional quantities will have to be added from time to time (approximately once each hour). Burns and Smith more recently [3] reported an explosion during their preparation of 20 gm ethyl azide following their precautions cited above for methyl azide [2]. The explosion took place just after approximately 0.5 ml of additional indicator solution was added. They postulated that either the acidic indicator or exposure to the ground glass joint initiated the detonation. The force of the detonation of this 20 gm ethyl azide left a 1-cm deep depression in their 16-gauge stainless steel hood floor and shattered the safety glass around the hood's fluorescent lamp. The present authors are not in a position to comment on either the validity of the hypothesis of Burns and Smith or their recommendation. Obviously, all reactions involving the preparation, use, and disposal of solvents and by-products of azides and related compounds

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239

must be carried out on a very small scale with suitable protection of personnel even if a particular reaction has been repeatedly carried out without incident. The avoidance of ground glass joints, the protection from strong light, and the use of dilute solutions (as with diazo methane preparations) are additional precautions suggested by Burns and Smith [3]. In the case of "triflyl" azide, the recommendation has been made that the compound not be allowed to be completely free of solvent and that it not be stored for any length of time [4]. Ethyl azidoformate could be distilled at about 100°C. It did not detonate until 160°C. On the other hand, the vapors of this azide are toxic, leading to vertigo, severe headaches, and sometimes vomiting [5]. Of the 1,2-diazobenzenes, the parent compound, 1,2-diazobenzene, could be detonated on an anvil with a hammer. However, the 3-methyl4-methyl, 4-methoxy, and 4-chloro derivatives were not said to be shock-sensitive [6]. These observations show that extreme care must be exercised in the handling and preparation of azides and their derivatives. In addition, sodium azide and hydrazoic acid must be handled safely. In working with sodium azide, the salt must not come in contact with copper, lead, mercury, silver, gold, their alloys, and their compounds. All of these form sensitive explosive azides. Azide salts must not be thrown into sinks or sewers since all azide salts are highly toxic, react with acids to form explosive, toxic, and gaseous hydrazoic acid, and react with copper and lead pipes. Azides and hydrazoic acid are thought to be more toxic than cyanides and hydrogen cyanide [7a]. Decontamination of rags, filter paper, solutions containing sodium azide, and apparatus which has been contaminated with sodium azide should be done by soaking, in a fume hood, with acidified sodium nitrite until the azides have been destroyed, followed by washing or other disposal [7b]. In general, the handling and disposition of azides must be in conformity with all appropriate laws and regulations. While the use of silver azide has been recommended in some syntheses, in most cases this does not appear to be necessary. In view of the explosive hazards associated with heavy metal azides, use of this azide is best avoided. In view of the general hazards of handling azides, the scale of reaction should probably be reduced considerably. The removal of unreacted alkyl halide with silver nitrate may lead to silver azide formation and should, therefore, be replaced by another procedure.

32

240

AZIDES

B. M E T H O D S 32-1. Preparation of /i-Butyl Azide | 8 |

n-QH 9Br + N a N 3

CH3OH

n-C 4H 9N 3 + NaBr

(3)

With suitable safety precautions, to a flask containing 34.5 gm (0.53 mole) of sodium azide in 70 ml of water and 25 ml of methanol is added 68.5 gm (0.50 mole) of w-butyl bromide while stirring at room temperature. The resulting mixture is heated and stirred on a steam bath for 24 hr. The bottom layer of «-butyl bromide disappears after this time and a top layer of crude Η-butyl azide forms. The crude azide is separated and then treated overnight with alcoholic silver nitrate to remove traces of butyl bromide. The mixture is then filtered, washed with water, and distilled behind a safety barricade to yield 40.0 gm 2 5 295 (90%) of w-butyl azide, b.p. 106.5°C (760 mm), n ?- 1.4152, d 0.8649. [NOTE: tf-Butyl azide and methanol form an azeotrope (b.p. 60°C) from which the azide is liberated by the addition of a saturated solution of calcium chloride.] 32-2. Preparation of Phenyl Azide | 9 |

(4) To an ice-cooled (0°C to -10°C) stirred flask containing 300 ml of water and 55.5 ml of concentrated hydrochloric acid is added dropwise over a 10 min period 33.5 gm (0.31 mole) of freshly distilled Phenylhydrazine. Phenylhydrazine hydrochloride crystals precipitate as they are formed. Addition of 100 ml of ether at 0°C is followed by the dropwise addition (25 min) of a solution of 25 gm (0.36 mole) of sodium nitrite in 30 ml of water. At all times the reaction temperature is kept below 5°C. The product is isolated by carrying out a steam distillation of the reaction mixture to yield 400 gm of distillate. The ether layer is separated from the distillate, and the water layer is extracted with 25 ml of ether. The combined ether layers are concentrated at 25°-30°C under reduced pressure. The residue is distilled under reduced pressure to afford 24-25 gm (65-68%) of phenyl azide, b.p. 49°-50°C (5 mm).

32

AZIDES

241

• CAUTION: Phenyl azide decomposes violently when heated at 80°C or above. Care must be taken that the bath temperature never exceeds 60°-70°C. The product should be stored in a cool place in brown bottles. Preparation 32-3 illustrates the preparation of a polyacrylazide from cross-linked Polyacrylamide. A similar procedure for the preparation of a polymeric acyl azide from a monodispersed poly(styrenecoacrylamide) latex is described in the patent cited in [11]. 32-3. Preparation of Cross-Linked Poly(acrylazide) (10) CH 2—CH

A- + N H 2N H 2 -—> -fCH 2—CH

C O N H 2/ , CH 2—CH

\ -V + H N 0 2

C O N H N H 2/ ,

CONHNH

> fCH2—CH \

-V-

CON3/,

(a) Preparation of Poly (Acrylhydr azide).

(6)

In a siliconized glass-

stoppered Erlenmeyer flask, 1 gm of cross-linked Polyacrylamide beads are allowed to swell overnight in an excess of distilled water equal to approximately 1.3 times the bed volume of the gel. The flask is then suspended in a constant-temperature bath maintained at 47°C. At the same time, a glass-stoppered cylinder containing six times the number of equivalents of the acrylamide in the resin of hydrazine hydrate is immersed in the constant-temperature bath. After about 45 min, the hydrazine is added to the swollen Polyacrylamide, a magnetic stirrer is inserted in the flask, the flask is stoppered, and the mixture is stirred at 47°C for 7 hr. In a fume hood, the gel is washed with 0.1 M aqueous sodium chloride on a Büchner funnel and finally by sedimentation. This washing operation is repeated until the aqueous supernatant solution is free of hydrazine. The gel is finally washed and suspended in a storage buffer at pH 7.3, which is 0.20 M sodium chloride, 0.002 M Na 2EDTA, 0.10 M boric acid, 0.005 M sodium hydroxide, and 6 5 χ 10~ M pentachlorophenol. The resin is reported to contain approximately 4 milliequivalents of hydrazide per gram of dry resin. (b) Preparation of Poly (Aerylazide).

About 50 ml of the poly-

mer from step (a) is washed with 0.1 M aqueous sodium chloride and 0.25 Ν hydrochloric acid and resuspended to a 32-ml volume with

242

32

AZIDES

0.25 N hydrochloric acid. The suspension is cooled to 0°C. Then 8 gm of crushed ice is added. The container is placed in an ice bath and, with efficient magnetic stirring, 4.0 ml of 1.0 M aqueous sodium nitrite is added. If a biochemical reagent such as a protein with a free amino group is to be coupled to the resin, about 90 seconds later, this reagent is added rapidly to the reacting system while maintaining a temperature of 0°C. Stirring is continued for the reaction period required for the specific protein involved (see [10] for typical examples). The excess unreacted azide is reconverted into the hydrazide and then to the stable acetyl hydrazide by adding 1.5 ml of hydrazine hydrate and stirring for 0.5 to 1 hr, followed by washing on a Büchner funnel in turn with 100 ml of 0.1 M aqueous sodium chloride, 100 ml of 0.2 M aqueous sodium acetate in which 4 ml of acetic anhydride was dissolved immediately before the washing, 100 ml of 0.1 M aqueous sodium chloride, 50 to 100 ml of 2 M aqueous sodium chloride, and a storage buffer. REFERENCES 1. P. A. S. Smith, " O p e n - C h a i n Nitrogen C o m p o u n d s , " Vol. 2, p. 214, Benjamin, New Y o r k , 1966. 2. M . E. Burns a n d R. H. Smith, Jr., Chem. Eng. News p . 2 (Jan. 9, 1984). 3. M. E. Burns a n d R. H. Smith, Jr., Chem. Eng. News p . 2 (Dec. 16, 1985). 4. J. Z a l o o m a n d D . C. Roberts, J. Org. Chem. 46, 5173 (1981). 5. W. Lwowski a n d T. W. Mattingiy, Jr., J. Amer. Chem. Soc. 87, 1947 (1965). 6. J. H. Hall a n d E. Patterson, J. Amer. Chem. Soc. 89, 5856 (1967). 7a. Lonza, Inc., Fairlawn, N e w Jersey, " S o d i u m Azide, Determination of Hydrazoic Acid and Azide in the Atmosphere of Azide P l a n t s " (October, 1983). 7b. Military Specification MIL-S-20552A. " S o d i u m Azide, Technical" (July 24, 1952). 8. J. H. Boyer a n d J. H a m e r , J. Amer. Chem. Soc. 11,951 (1955). 9. R. O. Lindsay a n d C. F . H . Allen, Org. Syn. Coll. Vol. 3, 710 (1955). 10. J. K. I n m a n and H. M . Dintzis, Biochemistry 8, 4074 (1969). 11. L. C. D o r m a n , U.S. Patent 4,046,723 (Sept. 6, 1977).