Ammonia as a nucleophile

A diverse group of secondary and tertiary amines are readily synthesized from the reaction of primary and secondary amines with allylic carbonates in the presence of preformed iridium metalacycles, but the direct synthesis of primary amines via iridium-catalyzed allylic amination requires the use of ammonia as a nucleophile. The asymmetric allylation of ammonia had not been reported until very recently, and it is not a common reagent in other metal-catalyzed reactions. Nonetheless, Hartwig and coworkers developed the reactions of ammonia with allylic carbonates in the presence of la generated in situ [89]. Reactions conducted in the initial work led exclusively to the products from diallylation (Scheme 16). Further advances in... 

Mechanism of multiple alkylation using ammonia as a nucleophile. 

Michael Reaction Section 20.10 Figure 20.6 Multiple Alkylation Using Ammonia as a Nucleophile Section 10.6 Figure 10.4... 

A nucleophile-induced ring transformation reaction of 2-pyranones was reported (Scheme 6) to result in a regioselective synthesis of 2-aminopyridines 21 or 2-pyridones 22 <05SL623>. Urea was used to generate ammonia as a nucleophile source. The reaetion of 23 (R=CN) was initially examined under elevated temperatures and solvent-free conditions. This system yielded a mixture of both 21 and the pyridone equivalent of 23, in equal amounts. The reaction conditions were modified to yield 2-aminopyridine 21 selectively as shown in Scheme 6. However, the only reaction found to be selective for 2-pyridone 22 formation is where the cyano group was replaced with an ester, shown in Scheme 6. Compound 24 was converted to pyridone 22 in good yield. 

The process can continue to give one other nitrogen-based product, the quaternary ammonium salt. The final composition of the reaction will consist of varying ratios of RNHg, RgNH, R3N, and R4N C1 . Because the ratio of products is difficult to control or predict, we avoid using an amine (or ammonia) as a nucleophile in nucleophilic aliphatic substitution reactions. 

A standard method for the preparation of an a ammo acid uses a bromo carboxylic acids as the substrate and aqueous ammonia as the nucleophile... 

Ammonia can act as a nucleophile toward primary and some secondary alkyl halides to give primary alkylamines Yields tend to be modest because the primary amine IS itself a nucleophile and undergoes alkylation Alkylation of ammonia can lead to a mixture containing a primary amine a secondary amine a tertiary amine and a quaternary ammonium salt... 

Addition of ammonia as a model nucleophile to nitrile oxides was studied by a semiempirical MNDO method, for fulminic acid and acetonitrile oxide (121). The reaction is exothermic and proceeds in two steps. The first (and rate-determining) step is the formation of a zwitterionic structure as intermediate. The second step, which involves transfer of a proton, is very fast and leads to the formation of Z-amidoximes in accordance with experimental data. Similar results were... 

The nucleophilic addition of alcohols [130, 204-207], phenols [130], carboxylates [208], ammonia [130, 209], primary and secondary amines [41, 130, 205, 210, 211] and thiols [211-213] was used very early to convert several acceptor-substituted allenes 155 to products of type 158 and 159 (Scheme 7.25, Nu = OR, OAr, 02CR, NH2, NHR, NRR and SR). While the addition of alcohols, phenols and thiols is generally carried out in the presence of an auxiliary base, the reaction of allenyl ketones to give vinyl ethers of type 159 (Nu = OMe) is successful also by irradiation in pure methanol [214], Using widely varying reaction conditions, the addition of hydrogen halides (Nu= Cl, Br, I) to the allenes 155 leads to reaction products of type 158 [130, 215-220], Therefore, this transformation was also classified as a nucleophilic addition. Finally, the nucleophiles hydride (such as lithium aluminum hydride-aluminum trichloride) [211] and azide [221] could also be added to allenic esters to yield products of type 159. 

You have read (Unit 10, Class Xll) that the carbon - halogen bond In alkyl or benzyl haUdes can be easily cleaved by a nucleophile. Hence, an allqrl or ben l haUde on reaction with an ethanollc solution of ammonia undergoes nucleophilic substitution reaction m which the halogen atom Is replaced by an amino (-NHJ group. This process of cleavage of the C-X bond by ammonia molecule Is known as ammonolysis. The reaction Is carried out In a sealed tube at 373 K. The primary amine thus obtained behaves as a nucleophile and can further react with allqrl halide to form secondary and tertiary amines, and finally quaternary ammonium salt. 

These optimistic views received a first blow by the discovery of another category of nucleophilic aromatic photosubstitutions occurring in liquid ammonia as a solvent and nucleophile. In this medium the nitroanisoles still show the pattern that had become familiar, i.e., photosubstitution of OCH3 by NH2 with preference for reaction at the position meta with respect to the nitro-group. However, nitrobenzene, dinitrobenzenes, and nitrohalogenobenzenes... 

For attack of F on acrylic acid, first a hydrogen bonded complex is formed which then proceeds to the transition state and then to a stable carbanion. The methyl in the methacrylic acid reduces stabilization of the carbanion as predicted. Subsequent studies using ammonia as the nucleophile indicated that attack proceeded by a rate-determining intramolecular proton transfer from the nucleophile to the ligand, assisted by a discrete water molecule that acts as a catalyst17. They predicted that acrolein underwent 1,4-addition, acrylic acid either 1,2- or 1,4-addition and acrylonitrile 1,2-addition. 

The mechanism for amide formation proceeds via attack by the ammonia molecule, which acts as a nucleophile, on the carboxyl carbon of the acid chloride or ester. The alkoxide ion that forms assists with the displacement of the chloride ion or alkoxy group. 

There are three groups of substrates for which SNH reactions are especially characteristic (i) neutral azines and azoles (ii) azinium and azolium salts and (iii) nitro-arenes. Their electron-deficiency and, thus, their ability to react with nucleophiles strongly differ from each other. Azinium salts are the more electrophilic and are able to add even neutral nucleophiles very easily. Triazines,. v-tetrazines and polynitro-arenes also possess high electrophilicity. At the same time substrates such as pyridine (82JHC1285, 72JA682) and cinnoline (03CHE87), at a low temperature (e.g. in liquid ammonia as a solvent), do not react even with sodium amide. It should also be... 

In it, the ammonia uses its lone pair of electrons to form a new bond to the proton and so it is acting as a nucleophile, thus, the water is acting as an electrophile. 

We can predict whether molecules are more likely to react as nucleophiles or electrophiles depending on the strength of the nucleophilic and electrophilic centres present. For example, ammonia has both electrophilic and nucleophilic centres. However, it generally reacts as a nucleophile because the nitrogen atom is a strong nucleophilic centre and the hydrogen atom is a weak electrophilic centre. 

The Hantzsch synthesis produces a reduced pyridine but there are many syntheses that go directly to pyridines. One of the simplest is to use hydroxylamine (NH2OH) instead of ammonia as the nucleophile. Reaction with a 1,5-diketone gives a dihydropyridine but then water is lost and no oxidation is needed. 

When the reducing agent can also act as a nucleophile, such as thiolate anion [18] (Figure 7.4) or ammonia sensitised by mercury [19] (Figure 7.5), functionalisation of the unsaturated, fluorinated intermediate can occur. 

Add chlorides also react with ammonia and 1° and 2° amines to form 1°, 2°, and 3° amides, respectively. Two equivalents of NH3 or amine are used. One equivalent acts as a nucleophile to replace Cl and form the substitution product, while the second equivalent reacts as a base with the HCI by-product to form an ammonium salt. 

The aryne intermediate is usually written with a triple bond and a delocalized aromatic system, as shown in 3-44. The anion in the side chain reacts as a nucleophile with the electrophilic aryne. The resulting anion, 3-45, can remove a proton from ammonia to give 3-46. Because the product has been reached, we usually stop writing the reaction mechanism at this point. However, in the reaction mixture, amide will remove a proton from the carbon a to the cyano group of 3-46. Only during workup will the anion be protonated to give back 3-46. 

In these reactions ammonia serves as a nucleophilic reagent, attacking the carbonyl carbon or sulfur and displacing chloride ion. In the process nitrogen loses a proton to a second molecule of ammonia or another base. 

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