Diazo-compounds

Diazo compounds are formed when an acidified aqueous solution of a salt of a primary aromatic amine is treated with a solution of sodium nitrite. The reaction which takes place in the case of aniline hydrochloride is represented by the equation,— 

The diazo compound prepared in this way from aniline hydrochloride can not be isolated, as it is soluble in water and decomposes when an attempt is made to obtain it by evaporation of the solution. In the use of diazo compounds to prepare other substances it is, in general, unnecessary to isolate them and the reactions are, accordingly, carried out in aqueous solution. When it is desired to obtain the diazo compounds in pure condition, they are prepared in a different way. In this method the salt of the amine is suspended in alcohol and treated either with amyl nitrite or with the oxides of nitrogen formed by heating arsenous acid with nitric acid. When reaction is complete, ether is added to precipitate the salt of the diazo compound, which is obtained in crystalline condition. 

The salts of the diazo compounds are soluble in water, and resemble inorganic salts in certain respects. Their solutions 

The diazo compound formed in this way is a strong base. 

All these facts lead to the conclusion that the diazo compounds contain a pentavalent nitrogen atom, as it is only when nitrogen possesses this valence that its compounds show the properties of bases and salts. In order to emphasize this conclusion and thus indicate the analogy between the diazo and ammonium compounds, the word diazo has been replaced by the word diazonium in naming the compounds which have been described above. The compound of the formula C6H5N2CI is, thus, benzenediazonium chloride its structure is represented by the formula,— 

Diazo compounds have the following structure and should be carefully distinguished from the azo compounds and diazonium ions discussed above  

The first step of the mechanism involves protonation of diazomethane  

The carboxylate anion then attacks the resulting methyl group, kicking out N2, which is a 

Another classic reaction of diazo compounds is the Wolff rearragement, where an a-diazoketone loses N2 to form a carbene, which spontaneously rearranges to a ketene  

The loss of N2 is mediated by heat, light, or a transition-metal catalyst such as Ag20. Typically, the unstable ketene is not isolated but is trapped by water (to yield a carboxylic acid) or another molecule in the reaction medium. 

Benzoylphenyldiazomethane was hydrogenated to 1,2-diphenylaminoethanol in ethyl acetate, but with uptake of 1 mol of hydrogen the intermediate benzil monohydrazone could be isolated in good yield (eq. 9.89). Hydrogenation of the hydrazone under the same conditions gave 1,2-diphenylaminoethanol in 60% yield. 

A mixture of DL-threonine and DL-allothreonine was prepared by the hydrogenation of ethyl diazoacetoacetate over paltinum oxide in 70% ethanol containing sulfuric acid (eq. 9.90). 2,4-Dimethylpyrrole-3,5-dicarboxylic acid diethyl ester was also obtained as a byproduct. 

Looker and Thatcher synthesized allophenylserine (DL-eryt/tro-P-phenylserine) in high yield by hydrogenation of methyl benzoyldiazoacetate over 5% Pd-C in 70% acetic acid (eq. 9.91).244 The hydrogenation was highly stereospecific, and the allophenylserine obtained did not reveal any of the diasteromeric threo form. The same reduction by a variety of chemical reducing agents led either to recovery of the starting 

Certain diazo compounds can be photolyzed with UV light to generate highly reactive carbenes (Reaction 48). Similar to nitrenes, carbenes can insert into active C—H or 

Formation with Wdtf Rearrangement to Reactive Ketene 

Some diazirines, particularly the 3-trifluoromethyl-3-aryldiazirines, can rearrange upon photolysis to a linear diazo derivative, similar in structure to the photosensitive end of the cross-linker PNP-DTP (Chapter 5, Section 3.12). These isomerized products themselves can be photolyzed to the reactive carbene. 

Carbene generation from photolysis of diazirine compounds leads to efficient insertion into C—or N—bonds and also causes addition reactions with points of unsaturation within target molecules. Diazirine-containing photoaffinity probes have 

Most references to the use of EDC describe the optimal reaction medium to be at a pH between 4.7 and 6. However, the carbodiimide reaction occurs effectively up to at least pH 7.5 without significant loss of yield. See Chapter 9, Section 3 for additional information on the properties of EDC conjugation using small peptides coupled to carrier proteins. 

Diazonium salts react with various nucleophiles in water (Eq. 11.62). ° In acidic aqueous solution, p-phenylene wdiazonium ion reacts with alcohols more rapidly than it does with water. ° In the presence of nucelophiles such as halides, the substitution products are obtained. Furthermore, diazonium salts of aromatic compounds are excellent substrates for palladium-catalyzed coupMng reactions such as the Heck-type reactions in water. 

Jr Carbene Formation Reactive Hydrogen Containing Compound Or Insertion with Covalent Bond Formation (Reaction 56) 

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The diazonium salts are by far the most important diazo-compounds. These are salts... 

Basic, forms a stable water-soluble dihydrochloride. Diazotization gives brown azodyes (Bismarck brown) owing to the coupling of the partially diazotized base with the excess of diamine. Is also used as an end component of many azo-dyes, readily coupling with one or two molecules of diazo compound. 

Aromatic nitriles (or aryl cyanides) can be obtained by methods (1) and (3). but not by method (2). In addition, aromatic nitriles can be prepared by two other methods, (a) from the corresponding diazo compound by Sandmeyer s Reaction (p. 189), (b) by fusing the corresponding sulphonic acid (or its salts)... 

Supplement 1952 2504-2665 Furfuracrylic acid, 300. Sulphonic acids, 667. Amines, 683. Hydroxylamines, 637. Hydrazines, 639. Azo compounds, 643. Diazo compounds, 661. Carbon-metal compounds, 663. 

Supplement 1953 3242-3457 Hydroxy-carboxylic acids, 190 In i doxylic acid, 226. Carbonyl-carboxylic acids, 284. i Sulphonic acids, 386 Quinoline sul-phonic acid, 390. Amines, 419 2-Aminopyridine, 428. Amino-carboxylic acids, 541 Tryp- tophane, 545. Hydrazines, 563. Azo. compounds, 572. Diazo compounds, 590. ... 

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

The majority of preparative methods which have been used for obtaining cyclopropane derivatives involve carbene addition to an olefmic bond, if acetylenes are used in the reaction, cyclopropenes are obtained. Heteroatom-substituted or vinyl cydopropanes come from alkenyl bromides or enol acetates (A. de Meijere, 1979 E. J. Corey, 1975 B E. Wenkert, 1970 A). The carbenes needed for cyclopropane syntheses can be obtained in situ by a-elimination of hydrogen halides with strong bases (R. Kdstcr, 1971 E.J. Corey, 1975 B), by copper catalyzed decomposition of diazo compounds (E. Wenkert, 1970 A S.D. Burke, 1979 N.J. Turro, 1966), or by reductive elimination of iodine from gem-diiodides (J. Nishimura, 1969 D. Wen-disch, 1971 J.M. Denis, 1972 H.E. Simmons, 1973 C. Girard, 1974),... 

Hofmann (1), of the Zurich School, was the first to have tried unsuccessfully to prepare the unsubstituted parent compound, selenazole much later, in 1955, Metzger and Bailly (2) were equally unsuccessful in trying to prepare selenazole from 2-aminoselenazole by reduction of the diazo compound,... 

Epoxidation of tfie double bond as weU as cyclopiopanation reactions witii diazo compounds and metallocaibenes are also well documented (31—34). 

The Fuji CopiArt monochrome proofing system is based on the photogeneration of color from leuco dyes or diazo-coupling (35). CopiArt includes both positive and negative working systems (Fig. 6). For the positive working system, a diazo compound (6) reacts with a coupler (7) as shown. 

Fig. 6. CopiArt proofing system (a) stmcture of positive working system, where A = organic base, = coupler, Q = microcapsule, and = diazo compound and (b) stmcture of negative working system, where A = photoinitiator, = leuco dye, Q — microcapsule, and...

From Diazo Compounds via 1,3-Dipolar Cycloaddition. This method has been utilized widely in heterocychc chemistry. Pyrazohne (57) has been synthesized by reaction of ethyl diazoacetate (58) with a,P-unsaturated ester in the presence of pyridine (eq. 12) (42). 

Nitrite can be deterrnined by reaction with sulfanilamide to form the diazo compound, which couples with /V-(1-naphthyl)ethylenediamine dihydrochloride to form an intensely colored red azo dye. Nitrate can be deterrnined in a similar manner after reduction to nitrite. Suitable reducing agents are cadmium filings or hydrazine. This method is useful at a nitrogen concentration of 10 -lO " M. 

Azo Coupling. The coupling reaction between an aromatic diazo compound and a coupling component is the single most important synthetic route to azo dyes. Of the total dyes manufactured, about 60% are produced by this reaction. Other methods iaclude oxidative coupling, reaction of aryUiydraziae with quiaones, and oxidation of aromatic amines. These methods, however, have limited iadustrial appHcations. 

It is possible for diazo compounds to attack both the ortho and para position of hydroxyl and amino coupling components when these positions are not already occupied. 

Oxidative Couplings of Heterocyclic Hydrazones. This method has opened the way to the preparation of azo derivatives of diazo compounds unobtainable by other means, ie, heterocycHc compounds ia which the diazotizable amino group is conjugated with the heterocycHc nitrogen atom as ia 2- and 4-amiQopyridine, compounds which do not normally yield stable diazonium salts (38). The reaction occurs as illustrated by equation 7 for the iateraction of (A/-methylcarbostyryl)hydrazone [28219-37-6] and dimethyl aniline the overall process is oxidation. 

Fast Color Salts. In order to simplify the work of the dyer, diazonium salts, in the form of stable dry powders, were introduced under the name of fast color salts. When dissolved in water they react like ordinary diazo compounds. These diazonium salts, derived from amines, free from solubilizing groups, are prepared by the usual method and are salted out from the solutions as the sulfates, the metallic double salts, or the aromatic sulfonates. The isolated diazonium salt is sold in admixture with anhydrous salts such as sodium sulfate or magnesium sulfate. 

The aza-transfer reaction between 3-hydrazinopyridazines and aromatic diazonium salts or heterocyclic diazo compounds affords the corresponding tetrazolo[l,5-6]pyridazines, while 3-hydrazinopyridazine 1-oxide gives 3-azidopyridazine 1-oxide (76TL3193, 76X725). 

On the other hand, unsaturated diazo compounds are thermally transformed by 1,1-cycloaddition into a bicyclic pyrazqle (141). Although reversibility of this cycloaddition is... 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Although the most general cycloaddition reaction of diazo compounds is that they react as 1,3-dipoles, recently some reactions have been reported in which they react as 1,2-dipoles,... 

This synthetic appproach has been used in a few cases for the preparation of pyridazines from diazo compounds and cyclopropenes. In general, cycloadducts (176) are formed first and these rearrange in the presence of acid or alkali to pyridazines (Scheme 98) (69TL2659, 76H(5)40l). Tetrachlorocyclopropene reacts similarly and it was found that the stability of the bicyclic intermediates is mainly dependent on substitution (78JCR(S)40, 78JCR(M)0582>. 

Tisler and Stanovnik Heterocyclic diazo compounds 80CHE443... 

Diazoindazole (51) is one of the few heterocyclic diazo compounds whose structure has been determined (78AX(B)293). The diazo group shows a substantial carbanionic character (51b). 

Diazo compounds react with alkenes to afford A -pyrazolines, which in turn izomerize to A -pyrazolines if there is a hydrogen atom a to the N=N bond (Scheme 54). In those cases where two possible ways of isomerization exist, the more acidic hydrogen migrates preferentially. The alkene configuration is conserved on the A -pyrazoline (stereospecificity) but the regioselectivity depends on the substituents of both the alkene and the diazo compound. 

Pyrazoles are formed when the diazo compounds react with alkynes or with functionalized alkenes, viz. the enols of /3-diketones. Pyrazolenines (353 Section 4.04.2.2.1) are isolated from disubstituted diazomethanes. Many pyrazoles, difficult to obtain by other methods, have been prepared by this procedure, for example 3-cyanopyrazole (616) is obtained from cyanoacetylene and diazomethane (7iJCS(C)2i47), 3,4,5-tris(trifiuoromethyl)pyrazole (617) from trifluorodiazoethane and hexafluoro-2-butyne (8lAHC(28)l), and 4-phenyl-3-triflylpyrazole (618 R =H) from phenyltriflylacetylene and diazomethane (82MI40402). An excess of diazomethane causes iV-methylation of the pyrazole (618 R = H) and the two isomers (618 R = Me) and (619) are formed in a ratio of 1 1. 

It was not their reactivity but their chemical inertness that was the true surprise when diazirines were discovered in 1960. Thus they are in marked contrast to the known linear diazo compounds which are characterized by the multiplicity of their reactions. For example, cycloadditions were never observed with the diazirines. Especially surprising is the inertness of diazirines towards electrophiles. Strong oxidants used in their synthesis like dichromate, bromine, chlorine or hypochlorite are without action on diazirines. Diazirine formation may even proceed by oxidative dealkylation of a diaziridine nitrogen in (186) without destruction of the diazirine ring (75ZOR2221). The diazirine ring is inert towards ozone simple diazirines are decomposed only by more than 80% sulfuric acid (B-67MI50800). 

Thermal conversion of diazirines to linear diazo compounds was postulated occasionally and proved by indirect methods. The existence of a diazo compound isomeric to diazirine (197) was proved spectroscopically on short thermolysis in DMSO (76JA6416). An intermediate diazoalkane was trapped by reaction with acetic acid, yielding the ester (198) (77JCS(P2)1214). 

Methylvinyldiazirine (199) rearranges at room temperature in the course of some days. Formation of the linear isomer is followed by electrocyclic ring closure to give 3-methyl-pyrazole. The linear diazo compound could be trapped by its reaction with acids to form esters, while the starting diazirine (199) is inert towards acids (B-71MI50801). 

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