Sourcebook of Advanced Organic Laboratory Preparations || HYDRAZINE DERIVATIVES, HYDRAZONES, AND HYDRAZIDES

14 HYDRAZINE

DERIVATIVES,

HYDRAZONES,

AND HYDRAZIDES

1. INTRODUCTION 2. SUBSTITUTED HYDRAZINES

14-1. Preparation of Ethylhydrazine Hydrochloride 14-2. Preparation of 2-Pentylhydrazine

3. HYDRAZONES 14-3. Preparation of Benzaldehyde />-Nitrophenylhydrazone

4. HYDRAZIDES 14-4. Preparation of Terephthalic Dihydrazide 14-5. Preparation of Polyacrylic Hydrazide

A he simple molecule hydrazine is capable of forming at least six classes of derivatives. Table I gives an overview of the methods of preparing many of these substituted hydrazines. In this connection it must be pointed out that the monomethyl- and monoethylhydrazines are usually prepared by special methods [1,2]. When a large excess of hydrazine is used the more general alkylation of hydrazine given here will also lead to mono-substituted products.

The six classes of hydrazine derivatives are:

1. Substituted hydrazine with a free amino group, e.g., the simple monoaliphatic and monoaromatic hydrazines and the 1,1-disub-

1. INTRODUCTION

136

From S. R. Sandler and W. Karo, Organic Functional Group Preparations, Vol. I, 2d ed. (New York, 1983), 434fT., by permission of Academic Press, Inc.

1 4 H Y D R A Z I N E D E R I V A T I V E S , H Y D R A Z O N E S , A N D H Y D R A Z I D E S 137

TABLE I SYNTHESIS OF SUBSTITUTED HYDRAZINES AND HYDRAZINE DERIVATIVES

Product type Reaction type Reactant Reagent References

Monosubstituted hydrazine

1,1-Disubstituted hydrazine

1,2-Disubstituted hydrazine

1,1,2-Trisubstituted hydrazine

Condensation Hydrazine Dialkyl sulfate 7, 16 (Excess)

Condensation Hydrazine Higher alkyl 16-18 (excess) halide

Condensation Hydrazine Activated aryl 19-21 halide

Condensation Primary amine Chloramine 22-26 Condensation Primary amine Hydroxyl- 15-15a

amine-O-sulfonic acid

Reduction N-A\ky\-N- — 27-35 nitrosoamine

Reduction Hydrazone of — 36, 37, 38 aldehyde

Reduction Hydrazone of — 17,21,39 ketone

Reduction Aromatic — 40-43 diazonium salts

Condensation Hydrazine Alkyl halide 18 (2 moles)

Condensation Secondary Chloramine 23-25 amine

Reduction Mtf-Dialkyl-tf- — 27-35, 44 nitrosoamine

Condensation Hydrazine Activated aryl 7 halide (2 moles)

Condensation Dihydrazide Alkyl halide(s) 36, 45, 46 Reduction Monosubstituted 36, 37, 38

hydrazone of aldehyde

Reduction Azo compounds — 47, 48 Reduction Aromatic nitro — 49

(bimolecular) compounds

Condensation Hydrazine Alkyl halide 18 (3 moles)

Reduction Disubstituted — 37 hydrazone of aldehydes

(continues)

138 14 HYDRAZINE DERIVATIVES, HYDRAZONES, AND HYDRAZIDES

TABLE I (Continued)

Product type Reaction type Reactant Reagent References

Reduction Monosubstituted hydrazone of ketones

— c

Reduction Acyl hydrazone of ketone

— 50

Tetrasubstituted hydrazine Condensation Hydrazine Alkylhalide

(4 moles)" 18

Reduction Disubstituted hydrazone of ketone

c

Oxidation Secondary amine

— 50a

Hydrazone Condensation Hydrazine Aldehyde or ketone

16, 51, 52

Condensation Hydrazine Aldehyde or ketone

50

Condensation Substituted hydrazine

Aldehyde or ketone

51,52

Exchange Substituted Hydrazine 53 reaction hydrazone

Hydrazide Condensation Hydrazine Ester 51,54, 55, 56 Condensation Hydrazine Acyl halide

b 57

Condensation Hydrazine Amide 58, 59 Condensation Substituted

hydrazine Esters c

Condensation Substituted hydrazine

Acyl halide c

"Excess of alkyl halide may lead to monoquaternized compounds [18]. ^Frequently leads of 1,2-diacyl hydrazines [36,45]. Suggested reaction procedures.

stituted hydrazines, sometimes referred to as Α ,̂Λ -̂disubstituted hydrazines or "unsymmetrically disubstituted hydrazines"

2. 1,2-Disubstituted hydrazines, frequently referred to as "hyrdrazo compounds" or "symmetrically disubstituted hydrazines"

3. Trisubstituted hydrazines 4. Tetrasubstituted hydrazines 5. Hydrazones 6. Hydrazides

Hydrazine and its derivatives are well known as reagents used for the identification of carbonyl compounds. Of these, phenyl-

14 HYDRAZINE DERIVATIVES, HYDRAZONES, AND HYDRAZIDES 139

hydrazine, 2,4-dinitrophenyl hydrazine, and Girard's reagent [(CH3)3N

+CH2CONHNH2]CL- are of particular importance. Many

heterocyclic compounds with two adjacent nitrogens, such as pyra-zoles and pyrazolines, may be considered hydrazine derivatives, and methods of preparation of hydrazine derivatives may be applicable to their synthesis. The detailed treatment of synthetic methods for such heterocyclic compounds is beyond the scope of this work, although a few examples of the synthesis of some heterocyclic compounds will be indicated.

References 3-14 are a selection of reviews on the chemistry of hydrazine derivatives.

Hydrazine itself may be subjected to a variety of facile substitution reactions because of its great nucleophilic character. It may react with alkyl halides and activated aryl halides to yield substituted hydrazines. With acyl halides, esters, and amides it may form hydrazides. With carbonyl compounds, hydrazones form. Since hydrazine is afunc-tional in nature, both amino groups may undergo reaction. In the case of the reaction of hydrazine with two moles of a carbonyl com-pound, the products are termed "azines."

Many of the characteristic reactions of hydrazine may also be carried out with substituted hydrazines to afford a wide variety of products. In the case of reactions of substituted hydrazine derivatives, azine formation is ordinarily not possible.

In the case of the reaction of substituted hydrazines, such as Phenylhydrazine with glucose or certain other carbohydrates, one molecule of Phenylhydrazine reacts with the terminal aldehyde group to form a phenylhydrazone. A second molecule of Phenylhydrazine oxidizes the penultimate carbinol grouping to a carbonyl and a third molecule of Phenylhydrazine converts this second carbonyl to a phenylhydrazone. This class of di-phenylhydrazones is called an "osazone," a series of compounds not discussed in the present chapter.

Substituted hydrazines can be prepared by the reaction of amines with chloramine and with hydroxylamine-O-sulfonic acid. Of these two reagents, hydroxylamine-O-sulfonic acid has been introduced more recently and the scope of its reaction is still being explored [15]. The present authors believe that this is a more convenient reagent than chloramine. By its use, not only mono- but also 1,1-disubstituted hydrazine should be preparable. The synthesis and utilization of N-substituted chloramines and hydroxylamine-O-sulfonic acids require further exploration.


• CAUTION: In working with hydrazine and many substituted hy-drazines, one must bear in mind that many of these compounds are highly toxic. They may also be carcinogenic. Hydrazine has also been suggested as a component in rocket fuel. Consequently, extreme safety precautions must be taken.

Several classes of hydrazines have been prepared by a variety of reductive procedures of 7V-nitrosoamines and hydrazones of various carbonyl compounds. The latter procedure is of particular value, since by the judicious selection of the carbonyl compound and of a substituted hydrazine, hydrazones may be prepared which can lead to new hydrazines with up to three different substituents.

Other functional groups which have been reduced to substituted hydrazines are azides, carbazates (acyl hydrazones), azo compounds, and ketazines.

Since aromatic diazonium salts may be reduced to mono-aryl-substituted hydrazines, a simple route to a vast variety of N-arylhydrazines is available.

The use of hydrazine and substituted hydrazines in the preparation of hydrazones by reaction with carbonyl compounds is well known.

Of some interest is the fact that hydrazides also react with carbonyl compounds in an analogous fashion. Since poly(hydrazides) can be prepared from polymeric esters, resins can be prepared which are capable of separating carbonyl compounds from organic mixtures. Such resins might be used in a "carbonyl-exchange" column.

Poly hydrazides can be converted to poly (azides). These polymers find application in affinity chromatography and other biochemical procedures.

The best method of preparing hydrazides is by the reaction of hydrazines with esters. Acyl halides and amides may also be re-acted with hydrazines. In the case of the Ing-Manske reaction, N-substituted phythalimides are reacted with hydrazine to generate a primary amine and the cyclic phthalhydrazide.

2. SUBSTITUTED HYDRAZINES

• CAUTION: All reactions involving hydrazine, its hydrates, or its salts are extremely hazardous. Hydrazine, its salts, and its hydrates are toxic and considered cancer suspect agents. Extreme care should be exercised in working with these and related compounds and their derivatives.


The monoethylation of hydrazines given here was found possible when an excess of hydrazine in ethanol was used Π 61.

14-1. Preparation of Ethylhydrazine Hydrochloride |16|

• CAUTION: Both hydrazine and diethyl sulfate are extremely toxic and cancer suspect agents.

In a hood, in a three-necked flask fitted with a mechanical stirrer, an empty distillation column, topped with a total reflux-partial take-off distillation head, an addition funnel, and means to maintain a nitrogen atmosphere are placed 35 gm (0.63 mole) of potassium hydroxide, 30 ml (0.93 mole) of anhydrous hydrazine (95% active), and 60 ml of absolute ethanol. This mixture is cooled in an ice bath while being stirred mechanically.

From the addition funnel, 33 ml (0.25 mole) of acid-free diethyl sulfate is slowly added while maintaining a low temperature. After completion of the addition, the mixture is heated in a bath to 165°C to separate a mixture of hydrazine and ethylhydrazine by distillation. The distillate is cooled and made strongly acid by cautious addition of concentrated hydrochloric acid. The precipitating hydrazine hydro-chloride is separated by filtration from the hot solution. The filtrate is then concentrated to half volume. A small amount of hydrochloric acid is added and the solution is allowed to cool. The precipitate that forms is washed in turn with small portions of concentrated hydro-chloric acid, alcohol, and ether. The product is then dried in a vacuum desiccator over calcium chloride. A further crop of product may be obtained by concentrating the mother liquors to yield a total of 21 gm (87%) of ethylhydrazine hydrochloride.

The free hydrazine (see warnings above) may be prepared in 80% yields by treatment of the hydrochloride salt with base.

14-2. Preparation of 2-Pentylhydrazine [15]

KOH CH3CH2—CH2—CH—NH2 + NH 2OS0 3H >

N H 2— N H 2 + (CH 3CH 2) 2S0 4

KOH CH3CH2NHNH2.HC1 + C2H5OH -I- KHS04 C2H5OH

(HCl) Ο)

CH3

CH3CH2CH2—CH—NHNH2 + KHS0 4

CH3 (2)


To a mixture of 46 gm (0.53 mole) of 2-pentylamine and 9.2 gm (0.164 mole) of potassium hydroxide in 150 ml of water, heated to reflux, is added dropwise with stirring over a \ hr period, a solution of 9.5 gm (0.084 mole) of hydroxylamine-O-sulfonic acid in 50 ml of water. The reaction mixture is concentrated to half volume under reduced pressure. The solution is then transferred to a separatory funnel, layered with ether, and 10 ml of 10 TV sodium hydroxide solution is cautiously added. The ether layer is separated, and the aqueous system is repeatedly extracted with ether. The combined ether extracts are dried with potassium hydroxide. After evaporation of the ether, the residual oil is fractionally distilled under reduced pressure. The product boils between 56°-60°C at 11 mm. The yield is not reported in the patent. However, yields normally run between 30% and 60% by this general procedure [15a].

In the procedure of Gever and Hayes [15a], the isolation of the reaction product involves conversion to the substituted hydrazone of benzaldehyde, separation of the excess benzaldehyde by steam dis-tillation, hydrolysis of the hydrazone, and the precipitation of the hydrazine as the oxalate salt.

3 . HYDRAZONES

The preparation of hydrazones by the reaction of hydrazine de-rivatives with carbonyl compounds is well known and extensively described in most laboratory manuals. A typical example, used in our laboratory, is the preparation of benzaldehyde /?-nitrophenylhydrazine [51] given below.

14-3. Preparation of Benzaldehyde p-Nitrophenylhydrazone [511

Ο

In a 22-liter flask, cooled in an ice bath, is placed 1000 gm (6.45 moles) of /?-nitrophenylhydrazine and 10 liters of methanol. The solution is stirred while 800 gm (7.55 moles) of benzaldehyde is added dropwise. During this addition, the temperature within the reaction flask is kept below 0°C by use of an ice-salt bath. After the addition of


benzaldehyde is completed, stirring is continued for 16 hr while the reaction flask is allowed to warm up to room temperature. The prod-uct is then filtered off and freed of excess benzaldehyde by repeated washing with cold methanol. After drying, the product may be recrystallized from ethanol. Yield 1484 gm (94%), mp 195°C.

A procedure using essentially the same approach but using a small amount of glacial acetic acid as a catalyst for the reaction has also been reported [52,60,61].

4. HYDRAZIDES

In general, hydrazides may be prepared by many of the methods analogous to those used in the preparation of amides. For example, hydrazine salts of carboxylic acids and reactions of hydrazine with esters, acyl halides, acyl anhydrides, and amides may be used to produce hydrazides. A reaction analogous to the Hofmann deg-radation is the formation of hydrazides from ureides (acylureas) [54] (Eq. 4).

ο ο ο II II NaOX II / 4X

R—C—NHC—NH2 > R—C—NHNH2 (4)

The preparation of hydrazides by interaction of esters and hy-drazine hydrate is quite straightforward and proceeds in good yields. In many cases, simple addition of hydrazine hydrate to the liquid esters suffices to cause the precipitation of the hydrazide [62]. If the esters are insoluble or solids, a more prolonged treatment is required usually in the presence of an alcohol, as in the preparation of tere-phthalic hydrazide given below:

14-4. Preparation of Terephthalic Dihydrazide [51,55)

Ο Ο

II II

C—OCH3 C—NHNH2

+ 2 Ν Η 2Ν Η 2· Η 20 > I + 2 C H 3O H + 2 H 20

C—OCH3 C—NHNH2

II II

ο ο (5)


CAUTION: Hydrazine hydrate is extremely toxic and a cancer sus-pect agent.

For convenient handling, a quantity of dimethyl terephthalate is pulverized in a blender. In a flask, 232.8 gm (1.2 moles) of dimethyl terephthalate is slurried with 2760 ml of methanol. To this reaction mixture is added a solution of 504 gm (8.4 moles) hydrazine hydrate (85%) in 240 ml of methanol. The composition is stirred for 16 hr at room temperature. The solid product is then separated by filtration. The solid is repeatedly washed with cold methanol and finally dried in a vacuum oven to yield 222 gm (95%), mp over 330°C.

Since methyl acrylate is difficult to polymerize without some cross-linking, the usual products isolated are somewhat cross-linked. Even the hydrazides prepared from a modest molecular weight polymer of methyl acrylate, which is not cross-linked, tend to cross-link on standing. The preparation below is an example of the preparation of a polymeric hydrazide.

14-5. Preparation of Poly acrylic Hydrazide (56]

C0 2CH,

+ „ Ν Η 2Ν Η 2· Η 20 -

—CH2—CH I

CONHNH,

+ CH3OH + H 20

(6)

CAUTION: Hydrazine hydrate is extremely toxic and a cancer sus-pect agent.

In an Erlenmeyer flask, 5 gm of polymethyl acrylate (molecular weight approx. 80,000), which has been pulverized, and 50 gm of hydrazine hydrate are warmed on a water bath until a homogeneous solution is formed. To this solution is added 500 ml of methanol containing 1 ml of glacial acetic acid. The product thereupon precipitates.

To purify the product, the polyacrylic hydrazide is dissolved in 50 ml of water and again precipitated with methanol. This procedure is repeated several times. The product is finally dried in a vacuum desiccator over sulfuric acid at room temperature. The product is stored in the cold in a vacuum desiccator with the exclusion of light. The stability of this polymer, as a non-cross-linked raw material, is poor. In general, this preparation must be carried out quite rapidly,


with a minimum amount of exposure to heat during the preparation and with a minimum exposure to methanol.

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Sourcebook of Advanced Organic Laboratory Preparations || HYDRAZINE DERIVATIVES, HYDRAZONES, AND HYDRAZIDES