The Reactions of Amines

Part I. The Reactions of Amines Oxidation, Reduction, Addition, Substitution, and Rearrangement Part II. Some Organophosphorus Chemistry 

He who shall teach a child to doubt, The rotting grave shall ne er get out. 

A brief introduction to the material here has been provided in Chapter 5 (Sections VI and VII). That material should be reviewed at this time. 

Foundations of Organic Chemistry Unity and Diversity of Structures, Pathways, and Reactions, First Edition. David R. Dalton. 

On the other hand, the chemistries of silicon (lying below carbon in the periodic table) and phosphorus (lying beneath nitrogen) are strikingly different. Phosphorus, like nitrogen, can be expected to be found as phosphine (PH3), and as with amines, substituted phosphines and phosphonium salts should be capable of formation. While it might be (correctly) anticipated that with more electrons the chemistry of phosphorus would be more complicated, it might also be (correctly) anticipated that some similarities could be found. 

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The reaction of amines with the 4-phenylazo derivative (228) results in their rearrangement into triazolines. Depending on the basicity of the amines and the size of the alkoxy group, three different triazolines (229. 230, and 231) are obtained (Scheme 117) (454. 459, 472). In all cases, the first step involves nucleophilic addition of the amine to the carbonyl group followed by ring opening and further ring closure. 

Section 20 14 Amides are normally prepared by the reaction of amines with acyl chlo rides anhydrides or esters... 

The reaction of amines with alkyl halides was seen earlier (Section 22 7) as a complicat ing factor in the preparation of amines by alkylation of ammonia... 

A simpler nonphosgene process for the manufacture of isocyanates consists of the reaction of amines with carbon dioxide in the presence of an aprotic organic solvent and a nitrogeneous base. The corresponding ammonium carbamate is treated with a dehydrating agent. This concept has been apphed to the synthesis of aromatic and aUphatic isocyanates. The process rehes on the facile formation of amine—carbon dioxide salts using acid haUdes such as phosphoryl chloride [10025-87-3] and thionyl chloride [7719-09-7] (30). 

Other approaches have explored the reaction of amines with dimethyl carbonate or its precursors (28). A reaction scheme for the production of polymeric MDI is as follows ... 

An alternative approach to thionitrosoarenes involves the reaction of amines with SCla. This method has also been adapted to the production of selenonitrosoarenes ArN=Se by using the selenium(If) synthon PhSOaSeCl as the Se source (Scheme 10.2). It is likely that SeCla, generated in situ in THF, could also be used in this process. The Diels-Alder cycloaddition of ArN=Se species with dimethylbutadiene gives 1,2-selenazine derivatives in low yields. 

The reaction is known to be complex, proceeding through a tetrahedral intermediate called a carbinolamine. Generalizing to the reactions of amines with carbonyls, the two-step reaction sequence is... 

Many of the reactions of amines are familiar from past chapters. Thus, amines react with alkyl halides in S 2 reactions and with acid chlorides in nucleophilic acyl substitution reactions. Amines also undergo E2 elimination to yield alkenes if they are first qualernized by treatment with iodomethane and then heated with silver oxide, a process called the Hofmann elimination. 

The reaction of amines with Fl+ ions has an interesting practical application. Amines of high molar mass, frequently used as drugs, have very low water solubilities. They can be converted to a water-soluble form by treatment with strong acid. For example. 

Determine equilibrium constants for the reaction of amines with strong or weak acids. (Example 22.8 Problems 27,28) 27... 

In the reaction of amines such as NH3, NH2NH2, MeNH2, C6HUCH2NH2, and Ph(OMe)NH2, only monosubstitution can be obtained even in the presence of a large excess of the amine. This is taken into account by the deprotonation of the acidic monosubstituted complex by free amine leading to an iminocyclohexadienyl complex. The latter cannot be subjected to nucleophilic substitution of the second... 

The reaction of amines with aryl halides requires a catalyst in most cases to initiate the reaction. There are several approaches that result in N-aryl amines. Treatment of cyclohexylamine with p-MeC6H4B(OH)2 and Cu(OAc)2 gave the N-aryl amide in 63% yield. Aryl halides react with amines in the presence of palladium... 

Nitrosamines are readily produced from the reaction of amines with nitrous acid, i.e., acidified nitrite (3), and are also produced vivo when amines and nitrite are administered, as reflected by tumor induction [reviewed in (3)], and the in vivo appearance of nitrosamines (2> ) Challis and Kyrtopoulos (5) showed that gaseous NO2 reacts directly with amines in neutral or alkaline aqueous solutions to produce nitrosamines and nitramines. The kinetics of the extremely rapid reaction of... 

The reaction of amines with acetylene or higher aUcynes has seldom been described. w-BuNH2 reacts with acetylene at 160°C in the presence of CdS04 or CuCl or ZnCk to give w-butylpyrroline (Eq. 4.57) [236]. 

The reaction of amines and acetylene takes a different course in the presence of Zn(OAc)2/Cd(OAc)2. Thus, for example, EtNHj gives N-ethylethylideneamine in moderate yield (Eq. 4.60) [250], not ethylvinylamine as Reppe et al. had reported earlier [251]. 

Sulfate monoesters can react by dissociative paths, and this is the favored path. Whether such reactions are concerted or involve a very short-lived sulfur trioxide intermediate has been the subject of debate. ° Benkovic and Benkovic reported evidence suggesting that the nucleophile is present (though there is little bond formation) in the transition state for the reaction of amines with p-nitrophenyl sulfate. Alkyl esters of sulfuric or sulfonic acids normally react with C-0 cleavage only when this is disfavored, as in aryl esters, does one see S-0 cleavage. Sulfate diester... 

Dobanol Ethoxy late [443], At least 16 Triton units with mass 910 were observed. A study of the reactions of amines and amine derivatives with scC02 using cSFC-MS was also reported [448], Both cSFC-APCI-MS and cSFC-ESI-MS of PEG 600 and PPG 425 were described [416]. Direct insertion probe (DIP) methodology was used for the structure analysis of the antistatic agent V,fV-bis-(2-hydroxyethyl)alkylamine. When analysed by SFC-MS coupling, the same sample could be separated into six components. The alkyl chains consist of saturated Cn, Ci4, C16 and C18 chains and of Cig chains with one double bond where 18 1 and 16 0 chains dominate. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

The comparison of the rate constants of these reactions with BDE of N—H bonds proves that the higher the BDE, the lower rate the constant. The rate constants of the reaction of amine with hydroperoxide calculated by the IPM method are listed in Table 15.18. The parameters of these reactions are given in Table 15.18. The values of activation energies for all reactions of the type... 

Angelici and Brink (40) have found that in the reactions of amine with trans-M(CO),(PPhMe2)2+ (M = Mn or Re), the rate of carbamoyl formation follows the order, n-butylamine > cyclohexyl-amine >, isopropylamine > sec-butylamine >> tert-butylamine, implying a strong steric effect in carbamoyl formation. A similar order has been observed in the rate of reaction of organic esters with amines to form amides (41). The data in Table III indicate that a steric effect may be operative in the Ru (CO) /NR3-catalyzed WGSR, since with tertiary amines the rate follows the order, NMeQ > MeNC.H > NEt > NBu0, which does not reflect the basicity of these amines. 

The reactions of amines with BENAs were discussed in several publications (464, 499, 521-523). Although there are no special studies on the reaction mechanism, the available data combined with the results in Reference 502 suggest a mechanistic model for this process (Scheme 3.243). 

The reactions of amines and dialkyl alkoxymethylenemalonates are most frequently used to prepare the aminomethylenemalonates. Dialkyl alkoxymethylenemalonates react smoothly with amines under a wide variety of reaction conditions, usually with high yields (Scheme 6). The reactions probably proceed by an addition-elimination mechanism. In some cases, the addition products have been successfully isolated. 

In the previous section, aminomethylenemalonates were obtained in the reactions of amines and alkoxymethylenemalonates. The latter were prepared in a separate step from dialkyl malonates and alkyl orthoformate. Aminomethylenemalonates can also be synthetized in a one-pot procedure, starting directly from the amine, dialkyl malonate, and alkyl orthoformate or its equivalent. 

Wolfbeis investigated the reactions of amines and orthoesters with different CH-acid molecules (81CB3471). When the reactions of aniline, ethyl orthoformate, and dialkyl malonates (2 mol) were carried out at 130-140°C for 4 hr, phenylaminomethylenemalonamates (245) were obtained (81CB3471). Similar reactions with aliphatic amines were unsuccessful. Phenylaminomethylenemalonic acid could not be prepared in the reactions of aniline, methyl orthoformate or orthoacetate, and malonic acid. When these reactions were carried out in 2-propanol, only amidines (246) were obtained. 

Generally, the reactions of amines and 2-acylmalonates afforded not only the corresponding 1-(substituted amino)alkylidenemalonates (301), but also carboxamides and diethyl malonate (39JA2890 54JIC711 77GEP2705446). 

This topic has been reviewed in The Chemistry of the Functional Groups series published in 19821. It is not the purpose of this chapter to provide a complete literature review. Rather, this chapter will discuss some of the new methods of measuring and interpreting kinetic isotope effects that have been used to determine the mechanisms of the reactions of amines and amine derivatives. 

In this section, you will learn how to predict the reactions of different functional groups. You studied the most common reaction of alkanes, combustion, in your previous chemistry course. For this reason, the reactions of alkanes will not be considered here. The reactions of amines and ethers will be left for a later chemistry course. 

The iridium-catalyzed reaction of primary amines with diols gave cyclic amines. The reaction of amine 109 with diol 110 in the presence of [Cp lrCl2]/NaHC03 catalyst gave heterocyclization product 111 (Equation 10.26) [50]. 

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