Ammonia substitution

Ammonolysis. Reactions involving ammonia. Ammonolysis of esters, acyl chlorides, and anhydrides give amides aniline is produced by ammonolysis of chlorobenzene. The reaction is analogous to hydrolysis, with ammonia substituted for water. 

The value of Foo for triethylamine (Foo = + 630 m.v.) appears to be identical with that for ammonia and the various substituted ammonias substitution thus appears to exert no effect on the moment of this molecule. 

HMDS is known as an ammonia substitute in the preparation of primary amides via ammonolysis since 1985. With the use of excess HMDS, the Pd-catalyzed aminocarbonylation of various aryl and vinyl iodides and triflates (e.g., 146, 148, and 150) has been successfully performed to give the corresponding vinyl and aryl amides (e.g., 147, 149, and 151, respectively) in good to excellent yields (Scheme 21). " ... 

Another solution is the use of formamide as the ammonia substitute.Thus, the Pd-catalyzed aminocarbonylation of (hetero)aryl halides with formamide as ammonia substitute as well as solvent under CO afforded the corresponding primary amides in moderate to excellent yields (Scheme 22). ... 

In connection with the aminocarbonylation processes described above, an apparent CO-free aminocarbonylation reaction of aryl and alkenyl iodides was reported using A, Wdimethylformamide (DMF) as the ammonia substitute in the presence of phosphorus oxychloride (POCI3) (Scheme 23). This reaction is so far restricted to DMF at present. 

As mentioned earlier, the synthesis of primary amides is rather challenging due to technical difficulty in handling gaseous ammonia. Thus, the use of ammonia substitutes such as HMDS and formamide has been studied (see Schemes 21 and 22). With the use of microwave irradiation, however, it has been shown that it is possible to generate both CO and ammonia at the same time for the synthesis of primary amides from aryl bromides. This protocol is very useful for laboratory organic syntheses, especially combinatorial syntheses. As Scheme 29 illustrates, the Pd-catalyzed aminocarbonylation of aryl bromides 200 with formamide (33.5 equiv.) in the presence of KOBu (1.5 equiv.) and imidazole (1 equiv.) with microwave irradiation for 400 s (6.7 min) gave the corresponding benzamides... 

The valency of the complex radicle is the same as that of the central metallic atom when the complex contains only ammonia, substituted ammonia, water, or other neutral group. For example, cobalt in eobaltie. salts is trivalent, and the cobalt complex with ammonia, Co(NI13)8 ", is likewise trivalent copper in cupric sulphate is divalent, and the copper complex, [Cu(NH3)4] , is also divalent. In the same wn.y [Co(NH3)5.H30] " and [Co(NII3)4.(II20)2] " are trivalent, as also [Co(NH3)2.en2]" and [Co.en3] ", where en represents cthyleucdiamine, CH NH2... 

S. Rideal noticed the peculiar effect of ammonia on the germicidal value of hypochlorites he said that the first rapid consumption of chlorine is succeeded by a slower action which continues for days, and that the germicidal action continues after free chlorine and hypochlorite have disappeared it appeared that ammonia substitution products are formed yielding compounds more or less germicidal. 

The o-Amb isomer 33 has been prepared from methyl 2-methylbenzoate (30) by benzylic bromination to give 31, followed by ammonia substitution and hydrolysis of the resulting phthalimidine 32 (Scheme 10)J6L79 ... 

The hydride-donating potential of 1,4-dihydropyridines has already been discussed in a mechanistic context in Section 1.3.2.3. Commonly available 1,4-dihydropyridines are the Hantzsch esters (7 X = OR), obtained from condensation of a -keto ester with ammonia and an aldehyde. By far the simplest syntheses of Hantzsch esters involve condensation of ammonia (substituted amines react in general poorly) and an aldehyde if a hydride equivalent at the 4-position is desired. The Hantzsch synthesis has been used in many guises, also to produce nonsymmetrical systems. The interest in these compounds as calcium antagonists has doubtless stimulated the extensive synthetic effort. ... 

Other Types of Addition.—It. may be well to consider two distinctly different cases of seeming unsaturation as indicated by the formation of addition products. When ammonia gas, or ammonia substitution products, viz., the alkyl amines, react with any acid, e.g., hydrochloric acid, addition takes place and the reaction is represented as follows ... 

Between nitric acid and ammonia, or between nitric acid and free nitrogen, stand the lower oxidation products of nitrogen, viz., nitrous and hyponitrous acids, or the lower oxides of nitrogen, NO2, N2O3, NO and N2O. In the same way nitric acid substitution products are reduced to ammonia substitution products, i.e., nitro compounds are reduced to amino compounds. 

Thus the regioselectivity in the ammonia substitution is relatively high at 400°C the thermodynamic equilibrium of the three aminotoluene isomers (1,2 1,3 1,4 = 32 51 17 [14]) is obviously not determining. The limited isomerization at 400°C also shows that a... 

Scheme 22 Cross-coupling of aryl halides and ammonia substitutes mediated by in situ generated Pd/NHC system...

Monoethanolamine appears to be mote vulnerable to oxidation than secondary and tertiary amines. Hofmeyer et al. (1956) have shown that MEA is subject to oxidative deamination that results in the formation of formic acid, ammonia, substituted amides, and high molecular weight polymers. 

Ligand-directed labilization is well documented for ammonia substitution into... 

The nitrochlorobenzenes are valuable dyestufTs intermediates. The presence of the nitro-groups makes the chlorine atom very reactive and easily replaceable. Treatment with ammonia or dilute alkalis substitutes an amino- or hydroxy-group for the chlorine atom and gives a series of nilroanilines and nilrophenols. 

Osmiamates, e.g. K.OSO3N (K20s04(0H)2 plus ammonia) are stable and related species, e.g. [Os NC ], can be formed by substitution. 

Preliminary indication of the presence of a phenol ester may be obtained by heating the compound with soda-lime esters of phenols and also aromatic hydroxy-acids usually give the phenol. (Likewise amides, Imides, nitriles, substituted hydrazines, uretheines, etc. eifiord ammonia.)... 

Now, contrary to popular opinions, this method need not be conducted in a sealed pipe bomb. Secondary amination by substitution is as much a reaction of opportunity as it is of brute force and heat. In fact, heating can tend to cause the reformation of safrole and isosafrole. So the simplest way to do this would be to use 500mL of ammonium hydroxide or alcoholic ammonia or, for those wishing to make MDMA or meth, 40% aqueous methylamine or alcoholic methylamine (to tell you the truth, methylamine is preferable in this method because it is more reactive that ammonia so yield will increase). This 500mL is placed in a flask and into it is poured a solution of 35g bromosafrole (30g phenylisopropyl-bromide) mixed with 50mL methanol. The flask is stoppered and stirred at room temperature for anywhere from 3 to 7 days. The chemist could also reflux the same mixture for 6-12 hours or she could throw the whole mix into a sealed pipe bomb (see How to Make section) and cook it for 5 hours in a 120-130°C oil bath. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Several substituted cyclohexane derivatives may also be obtained by the reduction of a benzenoid precursor. Partial reduction of resorcinol, for example, and subsequent methyla-tion yields 2-methylcyclohexane-I,3-dione, which is frequently used in steroid synthesis (M.S. Newman, 1960 see also p. 71f.), From lithium-ammonia reduction of alkoxybenzenes l-alkoxy-l,4-cyclohexadienes are obtained (E.J. Corey, 1968 D). 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

Retrosynthesis a in Scheme 7,1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischer cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves orf/io-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia. 

The amino group on sulfur in 133 may be replaced by substituted amines with evolution of ammonia to give compounds such as 134 (Scheme 68) (316). 

Asinger et a], have developed a simple preparative method for variously substituted A3-thiazolines by the action of sulfur and ammonia on ketones. 

Diamides and triamides have been obtained from the action of an aqueous saturated solution of ammonia on the corresponding ester (Scheme 18) (88). Amides can also be obtained by the Curtius (16) or Hofmann reactions (80). Thus the Curtius reaction with 2-substituted 4-thiazolecarboxylic acids gives the 4-acetamido compounds (16). 

Amines which are substituted derivatives of ammonia react similarly O O... 

The reaction of ammonia and amines with esters follows the same general mech anistic course as other nucleophilic acyl substitution reactions (Figure 20 6) A tetrahe dral intermediate is formed m the first stage of the process and dissociates m the second stage... 

Amines like ammonia are weak bases They are however the strongest uncharged bases found m significant quantities under physiological conditions Amines are usually the bases involved m biological acid-base reactions they are often the nucleophiles m biological nucleophilic substitutions... 

Nucleophilic substitution by ammonia on a halo acids (Section 19 16) The a halo acids obtained by halogenation of car boxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reac tive substrates in nucleophilic substitu tion processes A standard method for the preparation of a ammo acids is dis placement of halide from a halo acids by nucleophilic substitution using excess aqueous ammonia... 

Alkylamines are in principle capable of being prepared by nucleophilic substitution reactions of aUtyl halides with ammonia... 

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