Hydrazine in Organic Chemistry

Hydrazine in Organic Chemistry G. D. BYRKIT AND G . A. MICHALEK Mathieson Chemical Corporation, Baltimore, Md.

T h e organic reactions of anhydrous hydrazine, now conimercially available, as well as hydrazine hydrate, hydrazine salts, and other derivativesare reviewed, and an extensive bibliography is presented. The products include substituted hydrazines, heterocyclic hydrazines, hydrazino acids and esters, hydrazones, azines, hydrazides and their polycondensation products, azides, semicarbazide and thiosemicarbazide, semicarbazones and thiosemicarbazones, aminoguanidine, and heterocyclic rings produced by hydrazine synthesis. Potential uses are indicated in the fields of organic intermediates, pharmaceuticals, dyes, resins, insecticides, photographic developers, and explosives.

H

YDRAZINE has been known and studied as a valuable reagent for more than 60 years. Xow that it is commercially available, the vast but scattered store of knowledge of its reactions can be more extensively applied. (Anhydrous hydrazine, hydrazine hydrate, and dihydrazine sulfate can be obtained from Mathieson Chemical Corporation in commercial quantities; other salts, such as the dioxalate, hydrobromide, acid sulfate, thiosemicarbazide, and the hydrazides of organic acids, can be supplied in experimental amounts.) Hydrazine and its derivatives are eapecislly valuable in making coniplex nitrogen-containing proctuc~ts-for example, five- or siumembered heterocyclic rings containing one to four nitrogeri atoms are readily made and are useful for the preparation of dyes and pharmaceutical products. Aliphatic azo rompounds and complex aliphatic diazo compounds which are not readily obtained in other ways can be made in good yield. The strong but selective reducing power of hydrazine permits the preparation of amines and aldehydes from esters, diphenylethane derivatives, and methylene compounds from carbonyl compounds, as well as isocyanates, substituted ureas, amides, and amino acids. These products are useful in themselves and for further syntheses. Simpler hydrazine derivatives such as substituted hydrazines, hydrazones, hydrazides, and semicarbazides are useful as insecticides, antioxidants, and textile agents, in photographic developers, and in explosives. Their use as analytical reagents is well known. Resins are mad6 by polycondensation of many of these derivatives as well as by condensation of hydrazine itself with difunctional compounds. Only the typical reactions and those leading to products of obvious commercial value are reviewed here. Most of the organic reactions of hydrazine take place in solution and suitable concentrations of reagent are frequently obtained from hydrazine salts. Use of hydrazine solutions or the hydrate is implied in the following, unless it is specifically noted that the anhydrous reagent has been used. The organic reactions of anhydrous hydrazine have not been fully investigated. Until recently it was not available commercially and it was difficult to prepare in the laboratory. All indications are that it is a much more vigorous reagent than hydrazine hydrate-for example, it attacks cellulose a t 125" C. with liberation of ammonia (260), whereas hydrazine hydrate forms an addition product from which hydrazine is readily removed by vacuum or washing (58, 189). Aromatic hydrocarbons heated to 160" to 260' C. with anhydrous hydrazine are hydrogenated to the corresponding hydroaromatic compounds. Under the same condi-

tions polyvalent phenols, glycerol, erithrytol, dulcitol, and mannitol are oxidized (260). Hydrazine hydrate normally reacts only with the -OR group of esters to give hydrazides, but there is evidence that anhydrous hydrazine may also attack the =O portion of the molecule to form a heterocyclic ring (308). Preparation and properties of hydrazine itself have been reviewed ( 14,140,182,203, 309). SUBSTITUTED HYDRAZmES

Substituted hydrazines may be made by heating hydrazine with active halides, certain aromatic nitro compounds, compounds containing unsaturated, linkages, or hetmwyclic oxygen compounds. Any or all of the hydrogen atoms of hydrazine may be thus Substituted to form monosubstituted or hydrttzino compounds, RNHNH,, unsymmetrically disubstituted, HINNHI, symmetrically disubstituted or hydrazo compounds, RNHNHR, trisubstituted RzNNHR, or tetrasubstituted compounds, RsNNRa. ALKYLHYDRAZINES.Heaction of hydrazine with alkyl and aralkyl halides usually forms a mixture of mono- and unsymmetrically disubstituted hydrazines (145, 184, 350, 365), because alkylation normally takes place on the more basic of the two nitrogen atoms (314). An excess of hydrazine favors monosubstitution (129, 130). Further alkylation with substituents of low molecular weight normally leads to azinium salts, I12NNR&I. These resemble quaternary ammonium compounds, and those containing a long-chain substituent, 61% to C l ~show , comparable bactericidal action (365). Laboratory directions for alkylation of hydrazine are included in Westphal's work (566) and in Dreyfus' patent (130). Hydrazino compounds can also be made by the reduction of hydrazones or by reduction and hydrolysis of semicarbazones, a8 discussed below. Tri- and tetrasubstituted hydrazines are not readily formed by direct alkylation, but propyl, Butyl (365),isopropyl (220), and benzyl (146) derivatives have been made by realkylation under more vigorous conditions. Tetrasubstituted hydrazines are also made by heating symmetrical tetrazenes, obtained by oxidation of unsymmetrically disubstituted hydrazines (317). In some reactions with halides, reduction of halo compounds rather than formation of hydrazine derivatives occurs. Thus halogen is replaced by hydrogen when a-bromo derivatives of acetoacetic (190) and benzoyl acetic esters (196),bromodiketones (2%, d34), a-halo-a-nitro fatty acids (254),and chloronitromethanes (EV)are treated with hydrazine. AROMATIC HYDR.4ZINES. In general, only monosubstituted hydrimzino derivatives are formed by reaction of hydrazine with chlorine or bromine attached to aromatic or heterocyclic rings. Reaction occurs only if activating substituents, such as two or more nitro groups, are present in the aromatic nucleus. Thus, 2,Cdinitrophenylhydrazine,valuable reagent for identification of aldehydes and ketones, is obtained from hydrazine and 2,4-dinitrochlorobenzene (82) : C1

NO2

This is the commercial method of production.

1862

Yields are 80 to

bptember

lsso

INDUSTRIAL AND ENGINEERING CHEMISTRY

86% (6). Other dinitru- and trinitrohalobenzenes behave sim-

c

ilarly (88, 8Q0,994). Some of these compounds show insecticidal activity; 2,~initrophenylhydrazineis highly toxic to screw worms and codling moth, and picrylhydrazine is toxio to screw worms (146). Hydroxyhenzotriamles may be formed by action of alkali or an excess of hydrazine on o-iiitrophenylhydrazines(969,961,860). Their hydrazine salts are reported to be very explosive (969,860). Substituted phenylhydrazines having both halogen and nitro groups on the benzene ring can also be made from chlorodinitrobenzenes if the nitro groups are in the 3,4- position with respect to the halogen. Under these coiiditions, the %nitro group rather than the chlorine is rcplared by hydrazine (171,g31, 941). In absence of halogen, a nitro group may be replaced by hydrazine if there are sufficient activating substituents in the ring--e.g., 3,4-dinitrotoluene yields 3-hydrazino-4-nitrotoluene; 3,4,Btrinitrotoluene and trinitro-pxylene behave similarly (17'0, a&?). HETEROCYCLIC HYDRAZINES.Halogen attached to a heterocyclic ring frequently reacts readily with hydrazine. Thus, cy8nUriC chloride forms cyanuric trihydrazine (138):

1863

ester, CBICOBN=NCOIC,H~(118,314,837),which possesses extraordinary powers of adding to other unsaturated systems. With I compounds containing conjugated double bonds, as, for example, cyclopentadiene (117), addition takes place at room temperature in absence of catalyst, usually in the 1,4position of the conjugated system. With styrene, azodicarboxylio ester forms a bicyclic system (116). It also adds to aromatic hydrocarbons such as naphthalene (116,191, 338) or anthracene (190) and even to mono-olefins (a),amines (116,118), alcohols (198),and aldehydes (8). The aldehyde addition product can be hydrolyzed to the corresponding acid. Azodicarboxylic ester can be used to remove a methyl group attached to nitrogen in a secondary amine. The addition product is a crystalline triazane, which is then hydrolyzed by dilute acids: N-COIEt RNHCHs

+ N-COtEt II

-+

RNHCH2NC02Et hydrolysis HIbO2Et ----t NHCOzEt

RNHt

KHzNH-N

> / - X2H,

?=%C,

N '

CIC-N

SHZNHC-N

\

(118)

1NHNH.a

/

Hydrazinodiazines, triazines, and diazoles disclosed as intermediates for resins are made similarly (90-06). Preparation of & ' hydrazino-Snitropyridine from the corresponding chloride at mom temperature has been described (943, 898). Recent patents cover the conversion to a hydrazine group of any compound containing a pyridazine ring with a reaative substituent in 0- position to the N of the ring (68, 63, 186). Compounds such as Zhydrazinobenzothiazole, ,2""

+ CHzO + kHCOaEt

MISCELLANEOUS HYDRAZINE DERIVATIVES. Hydrazine reacts leas readily with unsaturated linkages than with many other groups. It does, however, add to pnitrocinnamic acid and simultaneously forme the hydrazide (149):

VN$-

and %hydrazinobenzoxazole, @-)D"HNHa,

made by treating the corresponding halogen, hydroxy, or sulfonic acid compounds with hydrazine, are intermediates for dyes and synthetic drugs (94). HYDRAZINO AcrDS AND ESTERS. Carbon dioxide and hydrazine in aqueous solution form carbazic acid (341,368). Organic carbonates react similarly to give hydrazino esters, NHsNHCOsR (114, 8448). Hydrazinocarboxylic esters from methyl, ethyl, and benzyl carbonates treated with bis-(chlorocarbonates) give bis-hydrazo esters, which in turn are oxidized with concentrated nitric acid to the corresmndinn bis-am esters. For example: (PhCHskCOa NzHI:H20 -%PhC&OCONHNH, (CICOOC~H~OCOC1) + ( P h CHpOCO N H N H C O O )2C sH4 -concd. p( HNOi PhCHaOCON=NCOO--~C&. The products

+

are claimed to induce vulcanization of rubber without heat (f39, 377). Aliphatic a-halo acids react with hydrazine to give a-hydrazino acids, RCH(NHNHt)COOH (89,100, 101), from which amiuo acids can be made by treating the esters of these compounds with sodium nitrite to give a nitrosohydrazine derivative whioh f o r m the amino ester on gentle heating (101). Chloroacetic acid and hydrazine yield mainly hydrazinodiacetic acid (16,87). Ita sodium salt is useful as an organic sequestering agent (868). Chloroformic ester and hydrazine form either hydrazino- or hydraaoformic ester, depending on the conditions of reaction. The latter may be oxidized by strong nitric acid to azodicarboxylio

Substituted hydrazines convert @-nitrostyreneto 6-hydrazinophenylnitroethane (881) and hydrazine hydrate adds to isopropylidene cyclopentanone to give a hydrazo derivative ($19). When a more reactive group such as an active halide, a carboxyl, or a carbonyl group occurs near an unsaturated linkage, the hydrazino, hydrazide, or hydrazono compound first formed may form a heterocyclic ring. Many examples of this are shown below. Hydrazine reacts with cyanohydrins to form hydrazo rompounds. Porophor N (74),used as a foaming agent for plastics and rubber, is made by treating acetone with hydrocyanic acid to give the cyanohydrin, (CH&C(CN)OH, which reacts with hydrazine to give the hydrazonitrile, (CH,)&( CN )NHNHC(CK (CH&. This is oxidized by chlorine to the corresponding azo compound, (CH&C(CN)N=NC(CN)(CH&, which evolves nitrogen at 120°, leaving (CHS)&(CN)C(CN)(CH~)~ according t~ the Wolff-Kishner reduction, discueaed below. Other types of aliphatic azonitriles are similarly prepared (66, 111, 869) and have also been found to act as initiators for vinyl and diene polymerization (66, 869). Ethylene oxide treated with an exceas of hydrazine forms hydroxyethyl hydrazine (81, 167,988,387). Substituted alkylene oxides behave similarly (31)-for example: CH&HCHCeH,

L'

+

N2H4 (90%) ----* CH,CH(OH)CH(CsHs)NHNHz. Patents claim that the condensation products of these hydroxyalkyl hydrazines with long-chain fatty acids are valuable textile agents (173,897). Substituted hydrazines are reported to be effective rubber softeners, Aliphatic hydrazines such as the pentamethylene derivatives are most effective. Phenylethyl-, monosubstituted aromatic and unsymmetric diphenylhydrazines are active, but symmetrical diphenyl- and tetraphenylhydrazines cause stiffening rather than softening of rubber (881,369). Polyalkyl hydra-

INDUSTRIAL AND ENGINEERING CHEMISTRY

1864

zines are reported to vulcanize rubber without sulfur, owing to their ability to decompose thermally to give free radicals (136). Small amounts of unsymmetrical hydrazines including dialkyl-, diaryl-, alkylaryl-, phenyl-, acetylphenyl-, quinolyl-, and beminophthalylhydrazines are added to Diesel fuel as ignition improvers to stabilize added organic peroxides (71). Speed and sensitivity of photographic emulsions are increased by adding di- or trisubstituted hydrazines to developers (386)or by dispersing water-insoluble hydrazine derivatives in the emulsions (333). Acidic gases such aa sulfur dioxide are separated from gaseous mixtures by absorption in solutions containing unsymmetrical hydrazines or hydrazine hydrate ($9).

2Ha0 CB&H=NN (CHa)CH( C H $ O I ) C ~ H ~ F CHsNHNHz.HzSB4

Aldehydes and free hydrazine normally form azines, RHC= NN=CHR, but excess hydrazine will produce a hydrazone, RCH=NNH2. Azines may also be obtained by heating 2 mole cules of hydrazone (84, 316). Ketones normally form hydrazones, but ketazines may be obtained, for example, by heating with excess ketone in acid solution (306, 346, 368). Substituted hydrazines form hydrazones, RR’C=NNHR” (R’ = H if an aldehyde is used) (366). Hydrazones are important for identifying carbonyl compounds. 2,CDinitrophenyl hydrazones offer advantages of higher and sometimes sharper melting points and lower solubility ( 4 , 6,46, 63,800,208, 244, 342). Both hydrazones and azines are cryti talline solids which can be hydrolyzed more or less easily to hydrazine and the carbonyl compound from which they are derived by boiling with mineral acids (316,342). In view of the increased supply of hydrazine, this method of separating and purifying mixtures containing aldehydes and ketones may be applicable to large scale work such as the recovery of flavoring agents and perfumes containing carbonyl groups. Hydrazones are also important in organic synthesis, Aliphatic diazo compounds may be made by oxidation of hydrazones or ketones. Benzophenone hydrazone, for example, treated with yellow oxide of mercury gives an 85 to 90% yield of diazodiphenylmethane (332):

+ 2CsHsCHO + CHsOH

REDUCTION OF HYDRAZONES A N D AZINES. Aliphatic azo compounds can be made by catalytic hydrogenation of azines using platinum black, colloidal platinum, or palladium. Further reduction yields the corresponding hydrazo compounds: RR’C=NN=CR’R

HYDRAZONES .4ND AZINES

Vol. 42, No. 9

H

+

RR’CHN=NCHR’R

H

+ RR’CHNHNHCHR’R

Yields of 76 to 90% are reported for a wide variety of alkyl, aryl, aralkyl, and cyclic azines (131,132, 141,229,230,330,846548,369). If a benzene ring or carboxyl group is present, reduction takes place more easily and can be effected with sodium amalgam (7.9,98,100,102,2i8, 379). Monosubstituted hydrazines are made by hydrolysis after the first step (230,368,379) or by reduction of hydrazones (98, 100, 102, 218, 830). Hydrazo compounds can in turn be oxidized to azo compounds by chlorine (211 ), air, iodine (18, 46, i41, 330), mercuric oxide (369),cupric oxide (230),and nitric acid (119). When nickel is used as the catalyst for hydrogenation, a mixture of amines is produced (240,676). Benzalazine, for example, gives 68% primary, 26% secondary, and 2% tertiary benzylamines. Aluminum amalgam also reduces aliphatic or aromatic azines; the product is usually a primary amine, although secondary amines may occasionally be formed (248). HYDRAZIDES

Hydrazine converts esters, acid chlorides, or amides to hydrazides which may be primary (RCONHNHz), diacyl (RCONHNHCOR), cyclic [R‘(CONH-)2], or substituted (RCONHNHR’). Hydrazides are usually prepared by treating the methyl or ethyl ester of the acid with hydrazine hydrate, They often form at room temperature, but it may be necessary to use This method is especially valuable for making the more complex heat or a solvent for more resistant or insoluble esters. A r e aliphatic diazo compounds (324). matic esters are less reactive than aliphatic. Acid chlorides are Hydrazones and semicarbazones of aliphatic aldehydes and frequently used; where the ester is extremely unreactive this ketones add hydrocyanic acid readily to give a-hydrazinc- or may be the only practical way of making the hydrazide. Organic semicarbazidonitriles, RR’C(CN)NHNHt. Saponification gives acids form hydrazine salts which, on fusing, split out water to give a-hydrazino acids (261, p. 209; 362, 363). Preparation of hydrazides. n-Aliphatic acids can be identified by means of the amino acids from these compounds has been mentioned previhydrazide, and melting points of the entire series from formic to ously. a-Hydrazino acids are also made from hydrazones of ustearic and of dicarboxylic hydrazides from glutaric to sebacic keto acids by reduction with sodium amalgam; similar reduction were published recently (226, 271). Primary hydrazides may of their azinea yields hydrazo acids: undergo the usual react,ions of a substituted hydrazine with aldehydes, ketones, active halides, double bonds, other esters, etc. KKHI NHNHn Smith includes an excellent review of the preparation of primary // NaHg hydrazides covering literature up to 1946 in his chapter on the RC& R COCOOH NnH4 +RC Curtius reaction (326). \ I n general, amides are less reactive than esters, but under COOH.NaHi ‘COONa proper conditions, high yields . have been obtained (158). HyNaHg drazide formation has been used 2RCOCOOH 4- N*H, +RC=NN= CR __t RCHNHNHCHR to cleave amide linkages in I COnHNzHd ‘ON’ natural Droducts. Lactone rings can us&lly be opened to giye a-Hydrazino derivatives of propionic and phenylpropionic hydroxy acid hydrazides (103)from which the lactone may be reacids and homologs as well as hydrazophenylacetic acid and its covered by treatment with hydrochloric acid. Aldonic acid lachomologs have been prepared in this way (100,108). tones are recovered from mixtures in this way (366). Preparation Methylhydrazine is usually made by methylating benzalazine of the hydrazide of dihydroisdysergic acid from dihydroergotwith dimethyl sulfate and then hydrolyzing (187,314, 360); aminineand anhydrous hydrazine has recently been patented (304).

+

-

INDUSTRIAL AND ENGINEERING CHEMISTRY

September 1950

Monosubstituted hydrazines react normally with esters or acid chlorides. Substituted hydrazides of pyrazine monocarboxylic

1865

on the sulfanilamide, and then treating with hydrazine (378). In making sulfapyridine, for example:

.Y

acids, T j C o N H " R , are claimed to be therapeutically active as hN9 stimulants for the cardiac, respiratory, and circulatory systems (860). Hydrazides containing a long alkyl chain are used as textile agents, especially as a leveling agent in dyeing ~ o o l . These may be made from a hydroxyalkyl hydrazine and a long-chain fatty acid, or by treating an acid hydrazide-e.g., stearic-with a n alkylating agent such as ethylene oxide (173, 387). The sulfonated phenyl hydrazide of stearic acid is' claimed to be an excellent softening agent for wool (160). Diacyl hydrazides are obtained by treating a primary hydrazide with an ester or acid chloride, by treating hydrazine with an excess of acylating agent (368),or by mild oxidation of primary hydrazides with iodine in acid or neutral solutions (76, 77, 811). Diacyl hydrazides have acid characteristics and form salts with alkalies which may be of the enol form (368), RC=NN==CR. dNa dNa Oxidation of these salts with iodine forms azo derivatives of acyls (339). Am derivatives may also be obtained by direct oxidation of the hydrazides (%3), although mild oxidation of primary hydrazides in alkaline solution gives aldehydes in yields up to 64% (811).

Reaction of hydrazine with anhydrides frequently yields sec-

ondary cyclic hydrazides, R

These are also formed

with o-dicarboxylic esters and some a- and &aliphatic diesters (386). Cyclic hydrazides may be considered as diketopyridazine derivatives. Maleic ester, for example, forms mainly the cyclic hydrazide, l,%dihydropyridazine-3,6-dione:

0

e

CHCOOH

I1

CHCOOH

+ Pl'rHd.HzO +

HC"

ti I

HC NH

v c II

Q This compound has recently been shown to have unique properties as a growth regulator for plants. Growth of grass treated with 2,4, and 8 pounds per acre was retarded for 1 to 2 weeks, 4 weeks, and over 2 months, respectively, without apparent injury. Normal growth was resumed after the quiescent period (307). Hydrazine converts alkyl phthalimides and other cyclic imides to an intermediate which is hydrolyzed to secondary cyclic phthalyl hydrazide and an amine:

This hydrazinolysis of alkyl imides has proved to be a valuable method for preparing complex amines such as those used in syntherJis of mt,imalarials (80, 88,8991). Aminoalkyl hydrazines are made similarly from haloalkylphthalimides (288). Winterbottom used the reaction in malting substituted sulfanilamides, starting with an imide-substituted benzene sulfonyl halide, replacing the halide with a primary amine of the substituent desired

-

ACO-NH I I I +H * N U S O 2 N H

.h?

0

Therapeutically active sulfanilamide derivatives of guanidine, thiazole, pyrimidine, pyridazine, pyrazine, tetrazole, thiadiazole, etc., have been made similarly. A number of sulfonic acid hydrazides SULFONYL HYDRAZIDES. have been used in making dyes and drugs. Aromatic sulfonhydrazides are used to develop azo dyestuff images in color photography (306). Dye intermediates are made by reducing nitroaromatic sulfonic acid hydrazides (388). Phthalocyanine sulfonic acid hydrazides, obtained from the reaction of hydrazine or substituted hydrazines with the metal phthalocyaninesulfonyl chlorides, are used as dyes and pigments. Yields of these are about 90% (148). Both primary and secondary sulfanilhydraside, N H I C ~ H ~ S O ~ N H Nand H ~ NH&HBOINHNHSO&~H~NH~, show bacteriostatic activity (194), and some of their derive tives are therapeutically active (133,134,180,866). Preparation of aromatic aldehydes from acids through the secondary benzene sulfonyl hydrazides has been studied by McFadyen and Stevens. The acid hydrazide may be treated with benzene sulfonyl chloride, or the acid chloride treated with benzene sulfonhydrazide. The resulting benzene sulfacylhydrazide is decomposed to aldeiiyde by heating with alkali carbonate in aqueous or ethylene glycol solution (836). Yields of aromatic aldehydes are frequently above 80%, but the method fails entirely in the aliphatic series. The reaction has been used with excellent yields for preparation of complex aromatic aldehydes in connection with the synthesis of thyronine (183) and flavonones (70), and for heterocyclic aldehydes in synthesis of analogs of vitamin BI (& 887). With heterocyclic acids, as with aromatic, the reaction takes place only when the carboxyl group is attaahed to the ring (887). CARBONYLDERIVATIW~ OF HYDRAZIDES. Primary hydrazides react readily with aldehydes and ketones to form compounds of the general formula RCONHN=CHR'R'. Identification of carhonyl compounds by substituted benzoyl and naphthoyl hydrazides is recommended by Sah and his co-workers, who have determined the melting points of many of these hydrazidehydrazones (60, 61, 818, 818, 848, 308, 303, 311, $&, 364). Girard's reagents, which are used in isolating naturally occurring ketones from the fats which accompany them, are hydrazides containing a quaternary ammonium group such as trimethyl acethydrazide ammonium chloride, MesN(C1)CH2CONHNH2, and acethydrazide pyridinium chloride, c N ( Cl)CHp CONHNHI. (169). They are used especially in making watersoluble derivatives of natural substances containing a carbonyl group, such as keto steroids and certain perfume and flavoring agents. The ketones are then recovered by hydrolysis (167,168, 876). They are also used in making water-soluble derivatives of pharmaceutical compounds--e.g., methyl naphthoquinone derivatives of Girard's reagent are described as water-soluble products having vitamin K activity (36).

'

INDUSTRIAL AND ENGINEERING CHEMISTRY

1866

Hydrazide-hydrazones containing a long chain are surface-active. Condensation products of stearic and other long-chain hydrazides with glucose, maltase, fructose, crotonaldehyde, and acetonesulfonic acid have been patented as textile assistants and wetting agents (64,65,178,329). Hydrazones of pyrazine monocarboxylic acid hydrazide show physiological activity as heart and respiratory stimulants (96). POLYCONDENSATION PRODUCTS

Resins are formed by condensing hydrazine with dicarboxylic acids, anhydrides, or esters--e.g., adipic anhydride or hexadecm e dicarboxylic acid. The polyhydrazide or a polyhydrazine salt first formed is chsnged by heat to clear stable resins which can be molded or drawn. These patents have been taken over by the Alien Property Custodian (866457). A different type of resin is made from dihydrazides of aliphatic dicarboxylic esters by heating under vacuum or in an atmosphere of nitrogen or hydrogen. Tn this case the product is said to consist of 4-aminotriazole groups connected by polymethylene chains-for example

r

N-N

1

L melted and then cold-drawn to several times the original length (258, 288). Other types of resins are made by condensing methyl methacrylate with hydrazine (148, 176) and from malonyldihydrazide in presence of sodium hydroxide (188). Resin intermediates are made by treating hydrazinodiazines or triazines with an acid or anhydride (96,ZOl)-for example:

iH2

NH,

i:

Vol. 42, No. 9

ACID AZIDES

Primary hydrazides are converted to acid azides by nitrous acid in cold aqueous solution: RCONHWHz

+ HNO? +RCONj + 2HsO

According to patents issued to the I. G. Farbenindustrie, propionic, stearic, benzoic, pchlorobenzoic, and 4-methoxybenzoic azides are useful as antiseptics and disinfectants (204). Under proper conditions azides and amines react directly to give amides. Hydroxyalkyl amides of d-lysergic acid which have properties similar to ergot are made from hydroxyalkyl amines and lysergic acid azides (336):

Polypeptides with antibiotic properties have been made similarly by coupling an amino acid ester with an amino acid azide prepared from the hydrazide (186). Production of resins from diamines and diazides hm been patented (280). Substituted benzoic and naphthoic acid azides are used by Sah and his co-workers for identifying amines. The melting points of many of the unsymmetric ureaa thus obtained have been published (297, 299, 302, 303). SEMICARBAZIDE AND THIOSEMICARBA ZIDE

Semicarbazide results from action of hydrazine on urea or on cyanates (86). Substituted hydrazines, ureas, or organic isocyanates form substituted semicarbazides. Reaction of hydrazine with urea takes place on heating to 100’ C. (85) or, better, hp rrflusing in amyl alcohol (862):

O=C

/“*

\

+ NzH+H,O +HZNNHCONH, + NH.,

NH?

Potassium cyanate and hydrazine salts form hydrazine cyanate, which is isomerized to semicarbazide:

‘ f Similar intermediates containing semicarbazide or carbohydrazide substituents have been patented (90-96), as well as hydrazine derivatives of five-membered rings (206). Recent patents claim resin intermediates by condensing a hydrazide with dicyandiamide. Infusible resins are obtained by treating the intermediate with formaldehyde ( S O , 321 ). Resins may also be obtained by heating alkylene dihalides and hydrazine (265). A large exces8 of hydrazine (6 moles) leads to alkylene dihydrazines (129, 130), but a smaller excess (2 moles) forms compounds of the type:

KCNO

+ N?Hd.HCI +HzNNHZ.HCN0 +HyNNHCONH2

Baker and Gilbert have shown recently that this reaction can proceed rapidly a t room temperature; the prolonged heating formerly used is unnecessary (19). The analogous reaction between hydrazine and thiocyanate is the only important method for making thiosemicarbazide (81, I,568). An excess of urea, cyanate, or thiocyanate may form the secondary hydrazine deriva0 0

II

I/

tive hydrazodicarbonamide (biurea), H*NCNHNHCNH2,or the corresponding hydrazodithiocarbamide (27,273,354,368). Recent work indicates that carbon monoxide and anhydrous hydrazine form semicarbazide at 50’ C. and 1000 atmospheres, at higher temperatures or pressures, ring compounds are formed (60). Semicarbazide is also made by reduction of nitrourea (206). 0

I/

These also form resins if soda is added to take up hydrochloric arid, or such dihydrazine compounds may be condensed with dibasic arids (858). Capillary active compounds of the general form RS02NHNR’CH2N(X)=Ra” are made by condensation of formaldehyde with a hydrazide of a carboxylic acid (208) or sulfonic acid (803)in presence of a tertiary base (867).

CSubstitutcd or bsemicarbazides, XH?.VHCNHR, are made from monosubstituted ureas, organic isocyanates, or isothiocyanates, or by treating a semicarbazone with an amine. Thus, phenylurea forms Cphenylsemicarbazide in abou t 40% yield (366). A number of substituted phenyl derivatives hiLve also been reported (23, 2’37-302). The reaction with organic isocyanates and isothiocyanates is general for both alkyl and aryl derivatives (23, 889, 361, 383). Aromatic and some aralkyl amines react with semicarbaaones at 180° to 180° C. to give Csubstituted semicarbaaones which can

INDUSTRIAL AND ENGINEERING CHEMISTRY

September 1950

be hydrolyzed to the corresponding semicarbazides: %C= NNHCONHs R’NHZ + R.&=NNHCONHR’ NH, hydrolysis H2NNHCONHR’ RzC=O. Acetone semicarbazone is usually used. Yields up to 80% (196) are reported for aromatic (88, 86,196) and aliphatic amines such as phenylethyl(S76),benzyl- (196, 376), xenyl- (88), and menthyl amines (874), paminoazobenzene (7S),and esters of 112- or paryl amino acids (374). Ketonic thiosemicarbazones react similarly but more slowly (17, 370). Alkyl hydrazines usually form %alkyl semicarbazides, N H r NRCONH, from cyanates, alkyl thiosemicarbazides from thiocyanates, and the corresponding 2,Pdisubstituted derivatives from organic isocyanates (66, 2761). Hydrazino esters ( l i s ) ,allylhydrazine (l67), and hydrazino derivatives of heterocyclic rings (848) form only 1-substituted semicarbazides. Thus D’Alelio treated a$nohydrazinodiazines and -triazines with cyanates, isocyanates, or thiocyanates to obtain resin intermediates (90,91) which may be condensed by formaldehyde under alkaline conditions (47):

+

+

RCOCOzH

1867

+ HPNNHCONHg +

+

P;”z b

HzS-C

88 I l y

+ KCNO ---t

C-XHNHz “2

b

Semicarbarides are fairly resistant to hydrolysis by dilute acids and alkalies, but are hydrolyzed to hydrazines by more concentrated solutions (887, S49). Thus monosubstituted hydrazines result from hydrolysis of 1-substituted semicarbazides, although mild treatment of semicerbazones with dilute acid hydrolyzes them to the Corresponding semicarbazides and carbonyl compounds (.%‘SO, 864). Semicarbazides and especially thiosemicarbazides are active reducing agents. Discoloration of aromatic amines or monohydric phenols is prevented by addition of 0.01% of semicarbazide (876). Thiosemicarbazides are used in conjunction with usual antioxidants to stabilize fats, oils, gasoline, fruit juices, photographic developers, etc. (68). Semicarbazide hydrochloride is used in photographic developers to increase speed and sensitivity of the photographic emulsions (368). Use of Pallylsemicarbazide as a sensitizer for photographic dyes has been reported (8OQ). Oxidation of semicarbazide hydrochloride is reported by Linch to yieId urazine (8&?, 333). 1-Substituted semicarbazides may be oxidized to azo compounds or to semicarbazones (864). Acid semicarbazides and thiosemicarbazides are oxidized by iodine in alkaline solution to semicarbazones of aldehydes containing one leas carbon atom than the original a-keto acid, but oxidation by Nessler’s reagent gives semicarbazones of the original keto acid:

+ RCH=NNHCONH*

alkaline soh. 1-Substituted semicarbazides and thiosemicarbazides are also formed by methods analogous to tho=, described above for making substituted hydrazines, especially by reactions with active halides and by reduction of semicarbazones. The semicarbazidodiazines and triazines mentioned above are also made from semicarbazide and the corresponding heterocyclic halide (90,91):

COz

+ + HzO

R is Ph-,

CHs-, PhCH2-, PhCHzCHz--, &naphthyl, etc. (48, 886). Diary1 ureas are formed from semicarbazide and aromatic amines. The first product is &substituted semicarbazide, which reacts with another molecule of amine with elimination of hydrazine (847, $63): RNHz

+ HZNNHCONHZ +H2NNHCONHR + NHX + RNHCONHR

+ HpNNH2

Thiocarbonyl chloride and an excess of semicarbazide form

thiocarbohydrazide-N,N’-dicarboxamide, S=C( N H N H C 0 N-

$’

H& which gives color reactions with certain metallic ions, espe-

P,

HCl

+

N N

I

II

0

Aliphatic and hydroaromatic semicarbazones are readily reduced catalytically with colloidal platinum; isopropyl, benzyl, and a number of terpene semicarbazides have been prepared in H this way: RR’C=NNHCONHg-+ RR’CHNHNHCONHt (864, 886). Sodium amalgam is effective if a benzene ring or other double bond stands next to the

\

C=N-

/

group (104, 814, 896).

Acid semicarbazides are obtained by reducing semicarbazones or thiosemicarbasones of ?-ketonic acids with sodium amalgam:

cially copper and cobalt, and may be used in microchemical analyses (86). Acyl semicarbazides analogous to hydrazides are formed from semicarbazides with esters, acid chlorides, and amides. Sulfonic acids behave similarly. A number of sulfanil semicarbazides and hydrazides analogous to the sulfanilamides have been prepared. Some of these are therapeutically active (188,184, 180,194, 666). Condensation of semicarbazide with dibasic esters, anhydrides, or acids forms resins (866,,978). Preparation of resin intermediates by condensing semicarbazide with dicyandiamide has been patented recently (S.90, 381 ). Formaldehyde and semicarbazide do not give a semicarbazone but condense to a resin claimed to be suitable for films, coatings, or molded articles (d07). The tendency of both semicarbazide and thiosemicarbazide to form heterocyclic rings is very strong. Thiosemicarbazide is especially reactive, inasmuch as it exists in the tautomeric forms, H2NNHC(=S)SH2 HzNNHC(SH)=NH. Five- or six-

IN D U S T R I A L A N D E N G,IN E E R IN G C H E M I S T R Y

1868

membered rings are formed very readily with dik‘etones, keto esters, halo esters, etc. Derivatives of thiosemicarbazides form many sulfur-containing rings. In soine cases semicarbazide reacts through the enol form to give oxygen-containing heterocy(#lice. Preparation of such rings is discussed below.

Fol. 42, No. 9

Considerable interest has recently been shown in the use of thiosemicarbazone of acetylaminobenzaldehyde, CHsCONHCe HWH=NNHC(S)NH2, and similar thiosemicarbazones in treatment of tuberculosis. This drug was developed in Germany during the war and is not patented in this country. I t is known commercially as Tibione (184).

SEMICARBAZONES AND THIOSEM[CARRAZONES HYDRAZODICARBONAMIDE

Seniictarbazones are generally used for identification of aldeH2KNHCONH2 + RCH= hydes and ketones: RCHO I’r”HCOSHz and R&O H2NNHCONH2-+ R&=NNHCO?;I12. The semicarbazones crystallize well, are not very soluble, and usually have well defined melting points, many of which are recorded in standard reference books. Th-y are useful for isolation as well as identification, because they can be hydrolyzed by dilute acid to recover the carbonyl compounds. Hydrogen cyanide adds to the double bond of semicarbazones to give a-semicarbazidonitriles which on hydrolysis yield a-hydrnzino arids (862,363)-for example:

+

(C“,),CSHNHCO?\“2

I

+

HOH

-+ (CH3)2CC02H + ( 2 0 2 + 2311 I NHXH2

CN

The amide group of semicarbazones is esterified when refluxed with alcohol to give hydrazones of hydrazinoesters; thus with b e n d semicarbazone and amyl alcohol: PhCH:SNHCONHt

+ CsHiiOH --+

PhCH:r\;NHCOzCJl,l

+ NHI

The reaction is said to be general (235). Sodium derivatives of thiosemicarbazones are readily obtained by treatment with sodium ethylate:

S R?(’=NNH!”HI

+ NaOEt + SNa

RiC=NiV=&NHI

SNa

I + EtOH (or Rl(‘-SSHC=NH)

Thioalkyl semicarbazones are obtained by treat ing these compounds with alkyl halides. p- or ?-halo esters, however, yield unsaturated esters by elimination of sodium halide, while a-halo esters condense to thiadiazole derivatives (17 , 370,872,373). Many semicarbazones and thiosemicarbazones are effective ihsecticides. Patents have been assigned to the Secretary of Agriculture covering insecticidal use of semicarbazones of aldehydes (161, 162), saturated aliphatic ketones (181), ketones containing an alicyclic (16.2)or aryl group (163), Pphenyl thiosemicarbazones of aldehydes containing aryl, aralkyl, and fury1 groups (&), an insecticidal mixture containing acetophenone semicarbazone (164), and substituted thiosemicarbazides (44). Laboratory and field tests of these and similar compounds are being made (146, 147, 2.9;. 818,944). Results so far indicate that most of the substituted semicarba-

rides are toxic or highly toxic. 1,l-Diphenyl thiocarbohydrazide is iou( toxic to mosquito larvae. Thiosemicarbazide is 98% toxic to culiche mosquito larvae, but thiosemicarbazide derivatives do not seem to be effective (146). There is considerable variation in the insectiridal effectiveness of seniicarbazones (146). In general, semicarbazones of ketones seem to be more effective than those of aldehydes. Acetone semicarbazone is toxic to a long list of pests. Other derivatives, effective against one or more pests, include semicarbazones of p-chloroacetophenone, benzcphenone, cyclopentanone, 2-pentanone, 2-but anone, benzaldehyde, and crotonddehyde.

Hydrazodicarbonami,$e, biurea, H2SCO?r’HXIfCONH2, and the sulfur analog, H2NCSNHKHCSXH2, are obtained wher~ semicarbazide or thiosemicarbazide solutions are boiled or allowed to stand for some time (318, 368). These compounds are also produced by action of hydrazine on an excess of urea (273), cyanate (36‘8),or thiocyanate (151, 154) or, together with aidazines, by thermal decomposition of semicarbazones (36, ,216). Substituted hydrazodicarbonamides, RSHCONHNHCONHR, are made by heating Csuhstituted semicarbnzides (195). Oxidation of hytlrazodicarbonaniide with chromic acid yields azodicarbonamide, HJJCOK=XCONH.! (99, 386), but oxidation with sodium hypochlorite forms hydrazoic acid (97). Polyarnidetype resins are obtained by condensation of hydrazodicarbonamide with dibasic esters, acids, anhydrides, or amides such as sebacic anhydride or adipamide (268). Condensation with formaldehyde yields water-soluble resins which may be hardened by heat and pressure (283) to products used in creaseproofmg fabrics (284). CARBOHYDRAZIDE AND THIOCARBOHYDRAZIDE

Carbohydrazide may be made by action of 2 moles of hydrazine on organic carbonates such as diphenyl carbonate (28,868):

RnCOs

+ 2NLHd +HQNNHCONHNH2 + 2ROH

As noted above, reaction of equimolar amounts of hydrazine and organic carbonates leads to hydrazino esters. Thiocarbohydrazide, H~NNHCSXHNMZ,is obtained from ethyl xanthate and hydrazine in alcoholic solution (70% yield) (179), or from hydrazine hydrate and thiocarbonyl chloride (26, 840). Hydrazine salts treated with thiocarbonyl chloride, however, produce s-dithiocarbimidothiourea, CS( SHNCS),, rather than thiocarbohydrazide (26). Substituted carbohydrazides and thiocarbohytirazides of the general formula RNHXHCONHNHR may be made by treating hydrazino-aminodiazines or triazines with urea, thiourea, carbonyl chloride, or thiocarbonyl chloride. They ale used as intermediates for pharmaceutical products, plarticizers, and resins. The latter are obtained by condensation with formaldehyde (92,93). Primary carbohydrazides undergo the usual reactions of a hydrazide, as might be expected of the -CONHNH2 group (48, 178, 368,371). They are used in making resins by condensation with polymethylene dibasic esters, acids, or anhydrides (125, 25.4, 266, 879). Carbohydrazide is reported to react with potassium

/NHxH \

ethyl xanthate to form SC ‘NHNH

ci3 (179).

i

AMINOGUANIDINE

NH

/I

Aminoguanidine, HZNCXHNHI, or the tautomeric form, NH?

I

rU”,C=SSHI, may be made by treating hydrazine with cyanamide, calcium cyanamide, sodium cyanamide, or S-alkyl thiourea (226,382, $83). Substituted aminoguanidines are similarly made from suhstituted hydrazines, from hydrazine with substituted Salkyl thiourea, or from amines with S-alkylthiosemicarbazide~.

September 1950

4

I

INDUSTRIAL AND ENGINEERING CHEMISTRY

The chemistry of aminoguanidine has been covered in a review of the literature to 1939 by Lieber and Smith (186). Reactions of aminoguanidine offer a number of possibilities for preparation of dyes. It may be diazotized in neutral solution and hot-coupled with the usual dye intermediates to furnish a series of azo dyes which possess good dyeing properties on silk and wool. Yield of the diazotization product, guanyl nitrosoaminoguanyltetrazine, is about 83% and of the dyes 50 to 85% (32a). Condensation of aminoguanidine with o-diketones such as acenaphthenequinone or isatin derivatives yields aminotriazines which dye wool (109). Aminotriazoles made by dehydration of aminoguanidine hydrazides can be diazotized to stable diazonium salts which yield azo dyes with naphthol and related aromatic substances. These dyes are soluble in dilute aqueous alkali hydroxides (986). h'itroaminoguanidine is made by treating nitroguanidine with hydrazine sulfate (977). Its lead, copper, and barium salts are explosives used as detonating charges in blmtirig caps. They are made from metal hydroxides and nitroaminoguanidine (7,10, 11,66,67). Nitroaminoguanidine itself may be ground in a mortar without detonation, but it explodes on heating. It has been recommended as a test for nickel: As little as 0.0002 mg. of nickel added to nitroaminoguanidine solution containing caustic gives a blue color (177). Aldehydes and ketones form nitroguanyl hydrazones which are recommended for identification of these carbonyl compounds (877,383,367). HYDRAZOIC ACID AND AZIDES

Sodium azide may be made by treating alkyl nitrites with hydrazine in presence of sodium hydroxide or sodium ethylate. Thiele obtained a 70% yield using ethyl nitrite (S61), improved yields are claimed from amyl nitrite, and butyl nitrite is reported to give yields of 78 to 84%: Audrieth has reveiwed the preparrttion and inorganic derivatives of hydrazoic! acid (IS). Heavy metal azides are used as detonators (8, 13,334,369). HYDRAZINE A S A REAGENT

Hydrazine is an important reagent in number of versatile reactions. By means of the Curtius reaction, arids may be converted through the corresponding hydrazides and azides to isocyanates, amines, urethanes, asymmetric ureas, or amides. The reaction has been used most frequently in making primary amines. Amino acids can be obtained from cyano acids or from substituted malonic acids; aldehydes and ketones from monosubstituted and disubstituted malonic esters. Although it has usually been used on a laboratory scale, the reaction is suitable for making pharmaceutical intermediates (199) and has been used in synthesizing vitamin Be (191) and histamine ( 1 4 9 ) . The extensive literature on the reaction has been reviewed recently by Smith (316). Hydrazine reduces simple nitro aromatics to the corresponding amines (81, 170, 9.96). Nitrobenzene, 0- and p-nitrophenol, mand p-nitrobenzoic acid (MI),and 4-nitrophthalir arid all give the corresponding amines. Curtius (81) states that only one nitro group of dinitro aromatics can be redueed. However, nitroaniline is reduced by hydrazine to the diamine (961). Huang-Minlon has shown recently that the rcdurtion takes plwe more readily if the reaction mixture is refluxed in a high boiling solvent such as ethylene glycol. Nitrotoluene is readily reduced in this way to the corresponding toluidine, but in the presence of potamium hydroxide it forms p,p'-diaminostilbene. Similar reduction of pnitropropylbenzene in the presenre of alkali yields 4,4'-diaminoa,@-diethylbibenzyl. This, on diazotization and heating with water, forms the synthetic estrogen hexestrol (298): Et

Et

1889

Similar compounds are made from ketones by treating with hydrazine to give the azine, which is reduced to the corresponding hydrazo compound and then oxidized to the azo compound. This on heating splits out nitrogen. Hexestrol, for example, is prepared in this way from phydroxypropiophenone: 20HCeH4C4

+ NzH4 +

&Ha

-

HOCsHd2HNHNHCHCsH4OH oxidation

At HOCsH4CHN=NCHCsHaOH

At

It or air

At heat

0 ' above 120

kt HOCeH4CH-CHC~H~OR

At

At

Oxidation and nitrogen elimination may be carried out in the same step by heating in a high boiling solvent such aa anisole or xylene in presence of air. Yields are reported to be high, in some cases 95 to 100% (330). An important example of the reducing action of hydrazine is found in the Wolff-Kishner reduction of aldehydes or ketones to the corresponding methylene compounds by heating the hydraeone or semicarbazone with alkali or sodium ethylate. This reaction has been reviewed recently by Todd (867). I t is particularly valuable with compounds of high molecular weight and in reducing furan and pyrrole derivatives, where the usual methods fail. A recent modificavm of the reaction using a high boiling solvent and sodium hydroxide makes the proceea applicable t o large scale work with yields frequently above 90%. I t is not necessary to isolate the hydrazone. The carbonyl compour,1 is refluxed with hydrazine hydrate and sodium hydroxide in a high boiling solvent such as ethylene glycol, and low boiling constit uenta are allowed to evaporate until the reaction mixture reaches the desired temperature (197,199). FORMATION OF HETEROCYCLIC RINGS

The great variety of heterocyclic rings containing one to four nitrogen atoms which can be made from hydrazine and its derive tives makes this a fertile field for investigation toward developing intermediates for dyes and pharmaceuticals. Difunctional compounds such as dicarbonyl compounds, keto esters, halo esters, etc., in which the two active groups are in the beta or gamma position are likely to undergo ring closure. Hydrazine derivatives such as semioarbazides, thiosemicarbazidea, and aminoguanidine are espeoially active. The various types of rings which can be made from hydrazine or its derivat,ives, and some of the reactions used in making them are reviewed very briefly below. Heterocyclics from aminoguanidine have been reviewed by Lieber and Smith (896)and so are not covered here.

FIVE-MEJIBERED RINGS. PYRROLE DERIVATIVES,

Diethyl ketazine is converted to diethyldimethylpyrrole by

INDUSTRIAL A N D ENGINEERING CHEMISTRY

1870

drazine or substituted hydrazines to give N-aminopyrroles (223, 922) and with semicarbazide to form N-ureidopyrroles. The urea groups can be removed by hydrogenation (34). Succinic acid forms a monohydraaide wit,h 2,4dinitrophenylhydrazine, which loses water on heating to give N-amino-2,4-diketotetrahydropyriole. Adipic and phthalic acids behave similarly (59).

R

Y-'?

1 /I .

THIAZOLE DERIVATIVES,

Dihydrothiazoles substi-

7-" tuted in the 2- position by a hydrazone or azine group can be made by treating a-halo ketones with thiosemicarbazide (37) or thiosemicarbazones (238). a-Halo esters react with hydrazodithiocarbonamide (370) or with sodium derivatives of thiosemicarbazones (372)or thiocarbohydrazones (570) to give tetrahydro derivatives, also usually substituted by %azine groups which can sometimes be hydrolyzed to keto groups. Maleic anhydride condenses with thiosemicarbazones to 2,4-diketo-Scarboxyrnethylthiazole-%azine. Hydrolysis with strong hydrochloric acid yields 2,4diketo tetrahydrothiazole acetic acid (239).

Vol. 42, No. 9

the normal cyclic hydrazide, but monosubstituted malonic esters under the same conditions form fused-ring, tetraketo pyrazopyrazoles (126).

n

I/ 1

OXADIAZOLE DERIVATIVES, . Diacyl hydrazides are N-N condensed to oxadiazoles by means of phosphorus pentoxide (568). Acid hydrazides treated with carbonyl chloride form 2keto-dihydro derivatives (160); those made from palm kernel fatty acid hydrazides are intermediates for detergents (169).

/I /I .

THIADIAZOLE DERIVATIVES,

Oxidation of thiosemi-

N-N

carbazones of aldehydes with ferric chloride or potassium ferricyanide yields 2-aminothiadiazoles (110). Therapeutically active sulfa drugs are made in this way from thiosemicarbazones with an acetyl sulfanilyl group substituted in the 4-position (215, 266). Ketonic thiosemicarbazones oxidized with hydrogen peroxide form 2,5-alkylidenehydrazinothiadiazoles (110). IminodihyI drothiadiazoles result from 4-substituted thiosemicarbazides with N acid chlorides (169). Hydrazodithiocarbonamide reacts with acetic anhydride to give diiminotetrahydro derivatives (176). P~AZOLE, ,AND ISOPYRAZOLE, ,DERIVATIVES. Hydrazine and carbon disulfide heated under alkaline conditions are reported to yield dithioketotetrahydrotetrazine (1779, but work in the authors' laboratories does not confirm this (246). / \ A \ Other investigators reported preparation of 2,SdithioketothiadiHydrazine, substituted hydrazines (112, 221 ), or hydrazides (15) azo1 under similar ronditions (62, cf. 85). form pyrazole derivatives from the enol form of @-diketones. Isopyrazoles may result from the diketo form with free hydrazine or semicarbazide (57,384). Pyrazoles are also made by acylation of simple hydrazones (156) or from hydrazine and a,@-acetylenic ketones or aldehydes (368). Hydrazine hydrate and malononitrile form 3,5-diaminopyrazole (251, p. 304). Dihydropyrazole derivatives are formed by treating a,@-ethylenicketones or aldehydes such as mesityl oxide or acrolein with hydrazine (219,368). They triazoles result from reaction of hydrazides and amides (319), may also be made from azines of the fatty acid series having a t from treating diacyl hydrazides with zinc ammonium chloride least one methyl group next to the azine; ring closure is brought (368),or from oxidation of aldehyde thiosemicarbazones with about by organic or mineral acids (83,89,144, 165). hydrogen peroxide (110). &Aryl- or alkyl-3-ureidotriazoles used as intermediates for dyes and pharmaceuticals are obtained from N hydrazine and an acyl dicyandiamide. These products can be \/ \/ hydrolyzed to 3-aminotriazoles (210). Nitriles heated with hydrazine form 4-aminotriazoles or dihydrotetrazines. AcetoniPYRAZOLONES, , may be made by the reaction of @-keto trile and propionitrile give mainly disubstituted aminotriazoles (261, pp. 73-6). 3-Phenyl-&mercapto-1,2,4triazole is obtained /\ by adding benzoyl isothiocyanate to an excess of hydrazine hyesters, such as acetoacetic ester or benzoylacetic ester, with hydrate (193), and 4-amino-3-mercilpto-l,2,4triazolefrom tetradrazine (174, 190), substituted hydrazines (155, 174, 368), or chlorodimethyl sulfide and hydrazine (137). Dihydrazides of semicarbazide (106, 107, 108). Acetoacetic ester and carbohyaliphatic dibasic acids heated under vacuum condense to linear drazide form an N-substituted pyrazolone together with other resins said to contain 4-aminotriazole groups connected by polyproducts (370). Hydrazine converts esters of a,@-acetylenicacids methylene groups in 2,5- positions (288). such as ethyl tetrolate to substituted pyrazolones (268); the corI responding ethylenic esters may form dihydropyrazolones or, in some cases, resins (148). Acetylenic nitriles condense with hydrazine hydrate to pyrazoloneimines ($51, p. 304). Ethyl cyanoacetate or ethyl-@-amino-p-ethoxyacrylate and hydrazines or DIKETOTETRAHYDROTRIAZOLES, Hydrazodicarbonmethylhydrazine form pyrazolones (174). Diketopyrazolidines, -N-

Yh

J-1

d-1

C Y

.

/

N

/v

O--CN

, result from

the action of hydrazine on disubsti-

/ tuted malonic esters in the presence of sodium ethylate. This is

amide splits out ammonia readily to form urazole (273, 364), whereaa hydrazodithiocarbonamide may split out either ammonia or hydrogen sulfide to give the 3,Sdithio or 3-imino-Lthio analogs (153, 154). Reaction of carbon monoxide and anhydrous hydrazine at 150" C. and 1000 atmospheres is reported to yield 4-amino-l,2,4-triazole-3-one;at 3000 atmospheres this is reduced to 4-amino-1,2,4-triazole (60). Guanylurea hydrochloride, H,NCONHC(=lr")NH,.HCI, heated with NZHa.HCI forms

s

3-imino-5-keto-triazole with minor amounts of fused rings (874). Aminoguanazole, 4amino-3,bdiiminotriazole,results from molecular proportions of cyanogen bromide and hydrazine, but an excess of hydrazine yields diaminoguanidine (861,p. 104). The reaction product of hydrazine with hydrazodicarbonamide or its S- analog is variously reported as 4amino-2,bdiketotetrahydrotriazole and 3,&diketotetrazine. Evidence seems to support the former structure (9, 86, 1 Y9). The same compound is obtained from hydrazine and hydrazoformic ester (3U). S IYINOTHIATRIAZOLES,

#

1m1

INDUSTRIAL AND ENGINEERING CHEMISTRY

September 19%

"=d '.N I I/ .

Thiosemicarbazide

-N-N treated with nitrous acid may condense to iminothiatriazoles or to the isomeric thioketotetrazoles. 2- or Csubstituted thiosemicarbasides give the corresponding N-substituted rings (168,163).

I

N

ylic acids may be considered as diketopyridazines (80,187,166, 307, 386). They are frequently obtained from anhydrides and may be made from an excess of the ester or acid chloride,

-b5-d THIADIAZINE DERIVATIVES, .

1 I/

,

Semicarbazide and ni-

N-N trous acid give bhydroxytetrazole or the isomeric 5-ketodihydrotetrazole (368). As mentioned above, thiosemicarbazide is reported to form the analogous thioketotetrazole under similar conditions (168). Hydrazides couple with diazobenzene in acetic acid solution to give RCONHNHN=NCeH6 (76,878),which is transformed into 1-phenyl-&substituted tetrazoles in 40 to 60% . . yield (183). SIX-MEMBEREDRINGS. PYRIDIXE DERIVATIVES,I

1'

Furfuraldehyde and hydrazine sulfate heated to 152-3 O C. yield a mixture of 3-hydroxy- and 2,5dihydroxypyridine (18).

/N\ PYRAZINE DERIVATIVES,

I

I.

Diacetalylamine, from

chloracetal and ammonia, is converted to pyrazine by hydrazine under pressure. Dihydroxymorpholine is formed aa intermediate and the heterocyclic oxygen is replaced by nitrogen. Yield is 78% based on diacetalylamine (884). Phenacyl hydrazine, from w-bromoacetophenone and hydrazine hydrate, undergoes autocondensation to an %membered heterocycle, followed by spontaneous ring contraction with elimination of 2 molecules of ammonia and addition of one of water to form 2,5-phenyl-3-ketodihydroxypyrazine (884).

e1

PYRIDAZINE DERIVATIVES,

or

b

b_

Hydrazine

/\/ \ - \-/ b

Cj

I

I

frequently converts 1,Cdiketones to 3,6disubstituted dihydropyridazines (64, 823, WU,32fi). As mentioned above, the products may be N-aminopyrroles or polyazines. Hydrazides react similarly with 1,4diketones to give N-acylated compounds (64). 3-Keto-4,BdimethyI dihydropyridazine is obtained from hydrazine and a-methyl-@-acetylacrylicacid; 2,4-dinitrophenylhydrszine forms an analogous N-substituted ring ( 1 ). The heterocyclic oxygen of furane derivatives may be replaced by hydrazine to give the corresponding dihydropyridazine derivatives (69, ,910). Secondary cyclic hydrazides of surcinic, maleic, and edicarbox-

Thiosemicarbazide

\N/ condenses with ethyl chloroacetate to %amino-5-hydroxy-1,3,4thiadiazine; 4substituted thiosemicarbazides form the a n a l e gous substituted amino compounds (38). o-Bromoacetophenone and thiosemicarbazide form %amino-5-phenylthiadiazine together with a hydrazonothiazole derivative (37). 2-Amino-Cmethylthiadiazole is obtained by hydrolysis, with concentrated hydrochloric acid, of the 2-ket&methyl thiazole-%azine made by condensing chloroacetone and thiosemicarbazones (838). N

\i TETRAZOLE DERIVATIVES,

4

-

x

3,5-Hydroxytriazines or

TRIAZINE DERIVATIVES,

the isomeric diketotetrahydrotriazines substituted in the 4- position by Me&-, PhCH2-, p-MeOCsH4-, PhCH1CH2-, or PhCH(0H)CH (Ph)- are obtained by alkaPhCH=CH-, line dehydration of semicarbazones of a-keto acids (4U, 41, 886). Thiosemicarbazones give the analogous dithioketotriazines (885). a-Diketones and semicarbazide form 3-keto-5,Bdisubstituted dihydrotriazines (33,106,11t?). N TETRAZINE

DERIVATIVES,

A_.

Reaction of nitriles

w

and hydrazine may lead to 3,5disubstituted dihydrotetrazines or to N-aminotriazoles (Y8,861,pp. 73-6). Acetonitrile heated with hydrazine hydrate yields a mixture of these derivatives, but anhydrous hydrazine forms dimethyldihydrotetrasine exclusively (861, pp. 73-6). Reaction of an alkyl carbamate with hydrazine yields 3,6-diamino-1,4dihydro-l,2,4,&tetrazine(338). p-Urazine, 3,6diketohexahydrotetrazine, is reported from uns and carbohydrazide (179),from sodium hypobromite oxidation ai hydrazodicarbonamide (836),and from carbon dioxide and hydrazine under elevated temperature and pressure (61). The monothio derivative is reported from thiocarbohydrazide and urea or potassium xanthate and carbohydrazide, and the dithio derivative from thiocarbohydrazide and potassium xanthate (179). There is considerable disagreement in the literature as to whether this compound is actually a diketotetrazine or a dike& aminotriazole. With most of the preparations, the aminotriazole structure seems probable, but because Guha's preparations from carbohydrazide did not react with carbonyl compounds, it is possible that he did obtain a six-membered ring ( 179, cf. 9). Production of the dithioderivative is also reported from hydrazine heated with an excess of carbon disulfide under alkaline conditions ( IYr), but other investigators obtained 2,bdithioketothiadiazole or dithiocarbaaic acid (68,86,840), HANDLING TECHNIQUE

Hydrazine should be handled with due caution. It is toxic and under certain circumstances flammable or explosive. To r e duce these hazards, the hydrate or dilute solution should be used in preference to the anhydrous material wherever possible. The liquid should be handled only in a well ventilated room (846).

1872

INDUSTRIAL AND ENGINEERING CHEMISTRY BIBLI0f;RAPIIY

TOXICITY. Hydrazine vapor is extremely irritating to the eyes; the inhaled vapor causes various effects, including dizziness and nausea. The effects are not immediately noticeable, but develop gradually over a period of borne hours. Severe exposure of the eyes to the vapor is reported to cause temporary blindness, lasting about a day; several days may be required for complete rwovery. The vapor may also cause dermatitis and other allergic symptoms in some individuals. The concentration and exposure times that cause the various physiological effects have not been definitely determined; and the effects of long exposure to low concentrations have not been clearly established. Efficient ventilation will prevent any harmful effects. If no hydrazine odor is noticeable, there will be no symptoms of exposure. No evidence of cumulative effeets has been found in these laboratories. When accidental spillage makes it necessary to enter an atmosphere containing hydrazine vapor, an ammonia mask and gastight goggles or a full-face mask should be worn. The effect of the anhydrous liquid on the skin is similar to that of strong acid or alkali and is very rapid. Any liquid that touches the skin should be washed off immediately with plenty of water and the affected area treated as for an alkali burn. Clothing on which the liquid has been spilled should be removed immediately. Rubber gloves, rubber protective clothing, and goggles or face shields should be worn whenever there is a chance of liquid splash (146). FIREAND EXPLOSION.Hydrazine reacts spontaneously and sometimes explosively with oxidizing agents. It is oxidized slowly by atmospheric oxygen and will ignite when exposed to air on porous or catalytic surfaces such as asbestos, carbon, or iron filings. Pure liquid hydrazine is stable, but the vapor, like other liquid fuelr, forms explosive mixtures with air or other oxidizing gases. At elevated temperatures and when the vapor is sufficiently concentrated, it may be explosive even in the absence of oxygen. EQUIPMENT. In the design of large scale equipment for handling concentrated anhydrous hydrazine, stainless steel 304 or 347, fabricated by Heliarc welding, is usually suitable. Copper is satisfactory if provision is made for padding with nitrogen. Glasslied steel is satisfactory, but unsupported glass is not recommended for large equipment because of the fire hazard in case of breakage. A11 large equipment in which concentrated hydrazine may be heated to 40” C. or over should be padded with nitrogen. “he equipment should be designed for working pressures sufficiently above the venting pressure to accommodate safely any premure developed as a result of the explosive decomposition of hydrazine vapor. When concentrated hydrazine is heated under vacuum, the ingress of air into the equipment is to be avoided. Large containers should be provided with water sprays or jackets for cooling in case of emergency. Accidentally spilled hydrazine should be flushed immediately with water. LABORATORY USE. When hydrazine is used rn a laboratory reagent and beromes diluted by solvents and reactants or largely converted into other products, these extreme precautions for handling anhydrous hydrazine may not be necessary. In the absence of experience to the contrary, it is safer to assume that the reaction products and mixtures are unstable and toxic. HOWever, many are stable and nontoxic. Chemists in these laboratories have had no difficulty in carrying out laboratory scale experiments safely in a hood. Some of the reactions are very rapid and provision is made for cooling. Slow reactions, on the other hand, can safely be refluxed in high boiling solvents in allglass apparatus. Reaction mixtures can also be distilled under vacuum with a nitrogen or ammonia blanket during the heating and cooling cycles. Thus, with due respect for its properties, hydrazine in all its forms can be safely handled.

Vol. 42, No. 9

Ajello, T., and Cusmano, S., G a m chim. ital., 70,765-70 (1940).

Alder, K.,and Noble, T., Ber., 76B,54-7 (1943). Alder, K.,Pascher, F., and Schmitz, A., Ibid., 76B, 2‘;-53 (1943).

Allen, C. F. H., J . Am. Chem. SOC.,52,2955 (1930). Allen, C. F.H., Org. Syntheses, 13,3&-7(1933). Allen, C. F. H., and Richmond, J. H., J. Org. Chem., 2, 222-6 (1937).

American Cyanamid Co., and Stevens, A. H., Brit. Patent 553,406 (1943).

Anon., Chem. Trade J . , 114,70-2(1944). Arndt. F.,and Bielich, F., Ber., 56,809-17 (1923) Ashley, K. D.,(to American Cyanamid Co.), U. S. Patent 2,251,101(1941). Ibid., 2,286,327(1942). Aso, K.,Bull. Inat. Phys. Chem. Research ( T o k y o ) , 18, 180 1 (1939). Audrieth, L. F., Chem. Revs., 15,169-224 (1934). Audrieth, L. F., et al., Chem. Eng. News, 26, 3746-9 (1948):

“Chemistry of Hydrarine,” New York, John Wiley & Sons, in press. Auwers, K. V., and Dietrich, K., J . prakt. Chem., 139,65-93 (1934).

Bailey, J. R.,and Read, W. T., J . Am. Chem. SOC.,36, 1747-66 (1914).

Baird, W.,Burns, R., and Wilson, F. J., J . C h a . Soc., 1927, 2527-34.

Baker, B. R., J . Am. Chem. SOC.,65,1572-9 (1943). Baker, E.M.,and Gilbert, E. C., Ibid., 64,2777-80(1942). Baldwin, A. W., J . Chem. SOC.,1929,2959-63. Bambas, L.L. (to Parke, Davis & Co.), U. S. Patent 2,389,127 (1945),2,450,406(1948).

Barber and W’ragg, J . Chem. SOC.,1947,1331-7. Barrk, R.,and Pich6, L.,Can. J . Research, 19B,158-71 (1941). Bayer, O., Herdieckerhoff, E., and Schindhelm H. (to I. G. Farbenindustrie), U. S. Patent 2,073,600(1937). Beckett, T., and Dyson, G. M., J . Chem. Sac., 1937,1358-62. Beiistein, “Handbuch der organischen Chemie,” 4th ed., T‘ol. 111,p. 98,Berlin, 6. Springer, 1921. Ibid., p, 116. Ibid., p. 121. Ibid., p. 195. Zbid., Vol. XXVI, p. 204, 1st Suppl. p. 60. Benoit, G., Bull. soc. chim. Frame, 6,708-15 (1939). Berger, H., J . prakt. Chem., 152,267-328 (1939). Biltr, 8., Ann., 339,243(1905);J . Chem. SOC.,mi, 673 (1905). Blaise, E.E.,Compt. rend., 172,221-3 (1921). Bockmiihl, M.,Schaumann, O., Bartholomaus, E., and Leditechke, H. (to Winthrop Chemical Co.), U. S. Patent 3,372,655 (April 3,1945). Borsche, W., etal., Bm., 34,4297,4299 (1901);37,3177 (1904); 38,831 (1905). Bose, P. K.,Quart. J . Indian Chem. SOC.,1, 51-62 (1924). Bose, P. K.,and Nandi, B. K., Ibid., 7,961-4 (1930);8,31113 (1931). Bottoms, R. G. (to Girdler Corp.), U. S. Patent 1,834,016 (Dec. 1, 1931). Bougault, J., Compt. rend., 159,83-5 (1914). Bougault, J., J . pharm. chim., 11, 5-21 (1915). Bougault, J.,and Popovici, L., Compt. rend., 189,186-8 (1929). Bowen, C. V.,U. S. Patent 2,354,192(July 25,1944). Ibid., 2,403,495(July 9,1946). Brady, 0.L.,J . Chem. Sac., 1931,756-9. Bretschneider, H., de Jonge-Bretschneider, A., and .\jtai, N., Ber., 74B,571-88 (1941). British Thomson-Houston Co., Brit. Patents 562,332,562,373 (1944). Brown, A, C.,Pickering, E. C., and Wilson, F. J., J . Chem. Soc., 1927, 107-12. Buchman, E. R., and Richardson, E. M., J . Am. C h e m Soe., 61,891-3 (1939). Buckley, G. D., and Ray N. H., J . Chem. SOC.,1949,115ti-60. Buckley, G . D., Ray, N. H., and Imperial Chemical Industries, Brit. Patent 622,955 (May 1949). Busch, Ber., 27,2518 (1894);Ger. Patent 81,431;Frzedlaender, 4. 1325 11894-7). ) Campbell, N. R., Analyst, 61,391-5 (1936). i54) Capuano, S., Caw. chim. ital., 68,521-7,527-32 (1938). (55) Carlisle, P. J., C h a . E ~ QNews, . 27,150 (1949). (56) Cattelain, E.,Compt. rend., 209,799-801 (1939). (57) Cattelain, E.,and Chabrier, P., Bull. soc. chim. France, 1947, 1101-3. (58) Centola, G., Cam. chim. ital., 68,831-5 (1938). (59) Cereao, J., and Olay, E., Analea soc. espdn. f l s . y qufm.. 32, 1090-9 (1934).

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INDUSTRIAL AND ENGINEERING CHEMISTRY

(SO) Chen, H-M., and Sah, P. P. T., J. Chinese Chem. SOC.,4,62-8

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(1936). (61) Chen, P., Ibid., 3,251-5 (1935). (62) Ciba, Ltd., Brit. Patent 629,177(1949). (63) Ciba, Ltd., Brit. Patent Application 32,350(1948). (84) Ciba, L a . , Swiss Patent 243,596(1947). (65)Zbid., 249,003,249,004 (1948). (66) Clark, LeR. V. (to American Cyanamid Co.), Can. Patent 435,873 (1946). (67) Clark, LeR. V. (to American Cyanamid Co.), U. S. Patent 2,405,189(1946). (68) Clerkson, R. G. (to E. I. du Pont de Nemours & Co.), U. S. Patent 2,396,156(1946). (69) Clauson-Kaas, N., and Limborg, F., Acta Chem. Scand., 1, 619-23 (1947). (70) Clinton, R. O.,and Geieaman, T. A., J. Am. Chem. SOC.,65, 85-7 (1943). (71) Cloud, G. H. (to Standard Oil Development Co.), U. S. Patent 2,304,242(1942). (72) Conrad, V. A., and Shriner, R. L., J. Am. Chem. SOC.,55,296770 (1933). (73) Crawford, A. B., J. Roy. Tech. CoZl. (Glaygozu).4,607-16 (1940). (74) Curtis, F. J., U. S. Dept. Commerce, OTS Rept., P B 200 (1945). (75) Curtius, T.,Ber., 23,3023,3029(1890). (76) Ibid., 26,1263-4 (1893). (77) Curtius, T.,J. prakt. Chem., 50, 27680 (1894); 51, 165,353 (1895);J. Chem. SOC.,68432,276,331(1895). (78) Curtius, T.,J. prakt. Chen.,52,272 (1895); J. Chem. SOC.,70 i, 39 (1896). (79) Curtius, T.,J. prakt. Chem., 62, 84-97 (1900); 85, 37, 137 (1912); J. C h . SOC.,78 i, 610 (1900); 102, 137, 307 (1912). (80) Curtius, T., J. prakt. C h . ,92,74-107 (1915). (81) Curtius, T.,et al., Zbid., 76,233,238,281301,301-30 (1907). (82) Curtius, T.,and Dedichen, J. prakt. Chem., 50, 251 (1894); J. Chem. SOC.,68 i, 29 (1895). (83) Curtius, T.,and Fosterling, Ber., 27,770 (1894). (84) Curtius, T.,and Fransen, Zbid., 35,3234(1902). (85) Curtius, T.,and Heidenreich, Zbid., 27, 56, 58 (1894); J. prakt. Chem., 52,486 (1895); J. Chem. SOC., 70i,143 (1896). (86) Curtius, T.,and Heidenreich, Bw., 27,2684 (1894). (87) Curtius, T.,and Huesong, L., J. prakt. Chem., 83, 249-78 (1911). (88)Curtius, T., and Mayer, M., J. prakt. Chem., 76, 369-400 (1907);J. Chem. SOC.,94 i, 53 (1908). (89) Curtius, T.,and Zinkeisen, J. prakt. Chem., 58, 310 (1898); J. C h .SOC.,76 i, 165 (1899). (90)D’Alelio and Underwood (to General Electric Co.), U. S. Patent 2,295,564(1942). (91) Zbid., 2,295,565(1942). (92) Zbid., 2,328,956,2,328,957(1943). (93) Zbid.,2,328,958(1943). (94) Zbid., 2,328,962(1943). (95) Zbid., 2,435,203(1948). (96) Dalmer, O.,Diehl, C., and Walter, E. (to Merck and Co.), Zbid., 2,176,063(1939). (97) Darapsky, A., Ber., 40,3033-9 (1907). (98) Darapsky, A., J. prakt. Chem., 67, 112-36, 164-92 (1903); J. Chem. SOC.,84 1,367 (1903). (99) Darapsky, A., J. prakt. Chem., 76, 444 (1907);J. Chem. Soc., 944 106 (1908). (100) Darapsky, A., et al., J. prakt. Chem., 96,251-327 (1917). (101) Zbid., 146,21!3-49 (1936). (102) Ibid., pp. 268-306. (103)Ibid., 147,145-60 (1936). (104) Darapsky, A.. and Prabhskar, Ber., 45,2620(1912). (105) De, S.C.,J. Zndian Chem. SOC.,7,3614 (1930). (106) De, S.C., W r t . J.Indian Chem. SOC.,3,3040 (1926). (107) De, 8. C.,and Dutt, N. C.. J. Zndian Chem. SOC.,5, 459-65 (1928). - - -- ,. (108) Zbid., 7,473-80(1930). (109) De, 5.C., and Dutta, P. C., Ber., 64B,2604-6 (1931). (110) De, 8. C..and Roy-Choudhury. S. K., J . Zndian Chem. SOC.. 5, 269-78 (1928). (111) De Bell. J. M., Gogmn. W. C., and Gloor. W. E.. “German __ Plastics Practice,” rev. ed., pp. 450-61, Springfield, Maw., De Bell & Richardson, 1946. (112) Dewar, M.J. S., J . Chem. Soc., 1944,615-19. (113) Diels, O.,Ber., 35,347 (1902). (114) Ibid., 47,2183-95(1914). (115)Zbid., 54B,213-26 (1921). (116) Diels and Alder, Ann., 450,237(1927). (117) Diels, O.,Blom, J. H., and Koll, W., Ibid., 443,242-62 (1925). (118) Diels, O.,and Fischer, E., Ber., 47,2043 (1914). (119) Diels, O.,and Fritsche, P.,Ibid., 44,3018-27 (1911).

.

1873

(120) Diels, O., Schmidt, S., and Witte, W.,Ibid., 71B, 1186-9 (1938). (121) Diels, O.,and Wackermann, H., Ibid., 55B,2443-50 (1922). (122) Diels, O.,and Wulff, C., Ann., 437,309-18 (1924). (128) Dimroth and de Montmolin, Ber., 43,2904(1910). (124) Domagk, G. (to I. G. Farbenindustrie), Ger. Patent Application 176,219(1943),176,745(1944). (125) Dorr, R. E., Moldenhauer, O., and Bock, H., Ger. Patent 700,864(1943). (126) Dox, A. W., J. Am. Chem. SOC.,54,3674-8(1932). (127) Drew, H. D. K., etal., J. Chem. SOC., 1937,1-7. (128) Dwwitt, J. G. N., and Young, D. P. (to British Celaneae), U. S. Patent 2,420,702(1947). (129) Dreyfus, Henry (to Celaneae House), Brit. Patent 594,453 (Nov. 12,1947). (130)Dreyfus, Henry (to Celanese Corm). U. 9. Patent 2.445.518 (1948). (131)Egorova, V. I., J . Gen. Chem. (U.S.S.R.), 6,1404-17 (1936). (132)Zbid., 9,1647-51 (1939). (133)Euler, H. v., Swedish Patent 115,560 (1945). (134)Euler, H. v., Ahlstrijm, L., and Hasselquist, H., Arkio. Kemi. Mineral Geol., 15B (21) (1942); Chem. Zentr., 1942 II, 59. (135) Fargher, R. G., and Furnew, R., J. Chem. SOC..1915,688-99. (136) Farmer, E.H., Trans. Faradag SOC.,38,360 (1942). (137) Feichtinger, H., 2.Naturforsch , 3b,377 (1948). (138) Finger, J. prakt. C h . (21,75, 103 (1907); J. Chem. Soc., 92i.298 (1907). (139) Flory,’P. J:, and Rabjohn, N. (to Wingfoot), U. S. Patent 2,469,819(1949). (140)Fogler, M. F.,P B 186, U. 5. Dept. Comm.. Office of Publica-

tions Bosrd.

(141) Foldi, 2.. and Foder, G., Ber., 74,58945(1941). (142) Fox, A. L. (to General Aniline and Film Corp.), Brit. Patent 613,782 (1948). (143) Fox, S. W., Chem. Reus.,32,54(1943). (144) Franke, Monatsh., 20, 855 (1899); J. Chenk. SOC.,78 1, 212 (1900). (145) Franaen, H., and Kraft, F., J. prakt. Chem., 84, 137 (1911); J.Chem. SQC.,100 i, 817 (1911). (146) Frear, D. E. H., “Catalogue of Insecticides and Fungicides,” Vol. I, 1947, Vol. 11, 1948, Waltham, Maw., Chronica

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(147) Frear, D. E. H., and Seiferle, E. J., J . Econ. Entomol., 40, 736-41 (1947). (148) Freri, M.,Atti ;Yocongr. intern. chim.,3,150-4 (1939). (149) Freri, M., and Solza, A., Atti accad. naz. Lincei. Classe S&. Ps,,m t . e nat ,29,691-5 (1939). (150) Freund, M., Ber., 24,4178 (1891). (151) Freund et al., Zbid., 26,2877 (1893); 28,946 (1895); 29,2500 (1896). (152) Freund, M.,and Hempel, Ibid., 28,74(1895). (153) Freund, M., and Schwarz, Ibid., 29,2491 (1896). (154) Freund, M.,and Wischewiansky, S., Ibid., 26,2877 (1893). (155) Frey and Hofmann, Monatsh., 22,762 (1901). (156) Friedel, C., and Combes, A., Bull. soc. chim., (3) 11, 115 (1894); Chem. Zentr., 18941,586. (157) Gabriel, S.,Ber., 47,3028-33 (1914). (158) Galat, A.,and Elion, G., J.Am. Chem. SOC.,65, 1566-7 (1943). (159) Geigy, J. R., A-G., Swiss Patent 215,042(1941). (160) Ibid., 243,098 (1946). (161) Gertler, S. I., and Haller, H. L. J., U. S. Patent 2,251,735 (1941). (162) Ibid., 2,374,479(1945). (163) Ibid.. 2,388,684(1945). (164) Ibid., 2,408,307(1946). (165) Gheorghiu, G.,BuZZsoc. chim. France, (4)47,630-9 (1930). (166) Gilbert, E. C.,J. Am. Chem. SOC.,46,2648-55(1924). (167) Gilman, “Organic Chemistry,” 2nd ed., Vol. 11, pp. 1470, 1511,New York, John Wiley & Sons, 1943. (168) Girard, A., and Sandulesco,G.,Helv. Chim. Acta, 19,1095(1936). (169) Girard, A.. and Sanduleaco, G., U.S. Paten+ 2,045,132(1936); Brit. Patent 431,165 (1935); French Patent 767,464 (1934). (170) Giua, M.,Qazz. chim. {tal., 49,II, 156-75 (1919). (171)Zbid., 52,I, 346-9 (1922). (172) GrBnacher, C.,and Sallmann, R. (to SociBtB pour I’industrie chimique iiBAle), U. S. Patent 2,355,911(1944). (173) Griinacher, C., Sallmann, R., and Frei, J. (to SociBtB pour l’industrie chimique B BiUe), Zbid., 2,371,133(1945). (174) Graham, B., Porter, H. D., and Weissberger, A., J. Am. Chem. SOC.,71,983-8 (1949). (175) Graves, G. dew. (to du Pont de Nemours & Co.), U. S. Patent 2,146,210(1939). (176) Guha, P. C., J . Am. Chem. SOC.,45, 1036-42 (1923). (177) Guha, P. C., Quart. J. Indian Chem. SOC.,1,141-9 (1924). (178)Zbid., 2,225-39 (1925).

1874

I N D U S T R I A L A N D E N G I N E E R I N G CHEMISTRY

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Vol. 42, No. 9

McLean, J., and Wilson, F.J.,J . Chem. Soc., 1937, 556-9. Ibid., 1939, 1048-50. Mailhe, A., Compt. rend., 170, 1120-3 (1920). Mangini, A., Gam. chim. ital., 66, 343-50 (1936). Mangini, A., and Colonna, M., Ibid., 68, 708-18 (1938). Mangini, A., and Frenguelli, B., Ibid., 69, 97-104 (1939). Martin, M. E., Kelly, K. L., and Green, M. W., J . d m . Pharm. Assoc.. 35, 220-3 (1946). (245) Mathieson Chemical Corp., unpublished reports. (246) Matzurevich, I., J. Russ. Phys.-Chem. Soc., Chem. Part, 57, 234-50 (1925). Maaourewi‘tch, H., Bull. SOC. chim., 35, 1183-6 (1924); J . Russ. Phys. Chem. Soc., 56, 55-60 (1925). Meng, K-C., and Sah, P. P. T., Science Repts. NatZ. Tsing Hila Univ., A2, 347-51 (1934). Merck, E., Ger. Patent 285,800 (1914). Ibid., 632,257; Friedlaender, 22, 622. Migrdichian,V., “Chemistry of Organic Cyanogen Compounds,” A.C.S. Monograph 105, pp. 73-6, 104, 209, 304, New York, Reinhold Publishing Corp., 1947. Mistry, S. M., and Guha, P. C., J . Indian Chem. SOC., 7, 793-7 (1930). (253) Mohr, E., J. prakt. Chem., 70, 290 (1904); J. Chem. Soc., 86 I, 1058. (254) Moldenhauer, O., and Bock, H., Ger. Patent 700,829 (1943). (255) Moldenhauer, O., and Bock, H.. U. S. Patent 2,349,979 ( 1 9 4 ) . (256) Ibid., 2,378,571 (1945). (257) Ibid., 2,383,880 (1945). (258) Moncrief, R. W., Mfg. Chemist, 18, 177-82 (1947). (259) Mtiller, E., and Hoffmann, W., J . prakt. Chem., 111, 293-306 (1925). (260) Mtiller, E., and Kraemer-Willenberg, H., Ber., 57B, 575-83 (1924). (261) Muller, E., and Zimmermann, G., J . prakt. Chem., 111, 277-92 (1925). (262) Munz, F. (to General Aniline and Film Co.), U. S. Patent 2,240,957 (1941). (263) Nacurewiez, M., Rocznikz’ Chem., 4, 295-7 (1924). (264) Neighbors, De W., etal., J . Am. Chem. SOC.,44, 1557-64 (1922). (265) Niemiec, E., Ibid., 70, 1067-8 (1948). (266) Northey, E. H., “Sulfonamides and Allied Compounds,” Tables 27, 31, 33, 42, New York, Reinbold Publishing Corp., 1948. (267) Oithner, L., Belle, G., and Schild, H. (to General Aniline and Film Co.), U. S. Patent 2,344,321 (1944). (268) Oskerko, A., M e m . Inst. Chem., Acad. S c i . Ukr. S . S. I%., 4, 195-202 (1937). (269) Overberger C. G., O’Shaughnessy, M. T.,and Shalet, H., J . Am. C’hem. Soc., 71, 2661 (1949). (270) Paal and Dencks, Ber., 36,491-7 (1902). (271) Paschke, R. F., and Wheeler, D. H., J . Am. Oil Chemzsts’ Soc., 26, 637-8 (1949). (272) Peckmann, H. V., Ber., 29, 2168 (1896). (273) Pellizzari and Cuneo, Ibid., 27, Ref. 407 (1894). (274) Pellizzari and Roncagliolo, G a m chim. ital., 31, 1, 487 (1901); Chem. Centr., 1901 11, 589. (275) Perkins, R. P., Dietzler, A. J., and Burdick, E. C. (to Dow Chemical Co.), U. S. Patent 1,973,724 (1934). (276) Petit, A., and Tallard, S., I n d . parfum., 3, 75-80 (1948). (277) Phillips, R., and Williams, J, F., J . Am. Chem. SOC.,50, 2465 (1928). (278) Phrix-Arbeitsgemeinschaft,Belg. Patent 443,948 (1942). (279) Ibid., 443,954 (1942). (280) Ibad., 444,274 (1942). (281) Piloty, O., Ber., 43,489-98 (1910). (282) Plisov, A. K.,Ukrain. Khem. Zhur., 3 ( l ) , Sci. Part, 125-31 (1928). (283) Pollak. E.. Austrian Patent 145.378 (1936). i284j Pollak, E. (to Alien Property Custodian), U. S. Patent, 2,072,408 (1937). (285) Popovici, L., Ann. chim., 18, 183-240 (1932). (286) Poth, E. J., and Bailey, J. R., J . Am. Chem. Soc., 45, 3001-8 (1923). (287) Price, D., May, E. L., and Pickel, F. D., Ibid., 62, 2818-20 (1940). (288) Prichard, W. W. (to E. I. du Pont de Nemours & Co.), U. S . Patent 2,395,642 (1946). (289) Pulvermacher, G., Ber., 26, 2812 (1893). (290) Purgotti, Gazz. chim. ital., 24, I 112 (1894). (291) Quin, D. C., and Robinson, R., J . Chem. Soc., 1943, 555. (292) Rath, C., U. S. Patent 1,733,695 (1929); Brit. Patent 255,811 (1925). (293) Robel, J., U. S. Dept. Commerce O T S Rept., PB 93767 (1948). (294) Robert, J. L., Rec. trau. chim., 56, 413-36, 909-18 (1937). (295) Rothenberg, R. V., Ber., 26, 2060 (1893). (296) Rupe, H., and Oestreicher, E., Ibid., 45, 30-8 (1912). (238) (239) (240) (241) (242) (243) (244)

September 1950

INDUSTRIAL AND ENGINEERING CHEMISTRY

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Sah, P. P. T., and Kao, I. S., Rec. trav. chim., 58, 459-64 (1939).

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18?5

(343) Sun, T-H., and Sah. P. P. T., Science Rept. Natl. Tsing Hua Univ., (A)2, 359-63 (1934). (344) Swingle, M. C., Phillips, A. M., and Gahan, J. B., U. S. Dept. Agr., Bur. Entomol. Plant Quarantine, E-261 (1944), E-634 (1945). (345) Taipale, K. A., Ber., 63B, 243-8 (1930). (346) Taipale, K. A., J. Russ. Phus. Chem. SOC.,Chem. Part, 54, 638-72 (1922-3); 56, 81-107 (1925); 57, 487-548 (1925); Ber., 56B, 954-62 (1923). (347) Taipale, K. A., Gutner, M. .4.,and Remiz, E. K., J. Gen. Chem. (U.S.S.R.1. 7. 1378-89 (1937). (348) Taipale, K. A., and’usachev, P. V.,J.’Russ. Phgs. Chem. Soc.. 62, 1241-58 (1930). (349) Thiele, J., Ann., 270, 7, 10 (1892); J. Chem. SOC.,62, 1295 f18!22\.

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RECEIVED February 17, 1950.