Mechanism of Secondary Amine Catalysis

The following section presents the energetic details of the formation of such activated substrates as well as how the stereoselectivity is imparted in the subsequent step of the reaction. The illustrations generally revolve around simple amines, pyrroUdines, and proline. Though a broad range of substrates has been considered, to maintain some degree of uniformity the substrates described here are generally simple aldehydes, ketones, nitroolefins, and other activated olefins. 

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Figure 9. Alternative mechanism for catalysis of secondary amine nitrosation by aryl nitroso compounds, su ested by G. Krow (private communication)...

A similar mechanism has been proposed for the oxidation of secondary amines to imines using catalytic Ru2( i-02CMe) Cl and O2 in toluene [108]. The substrate scope includes a number of five- and six-membered cyclic amines, including tetrahydroquinolines, tetrahydroisoquinolines, and indolines. Dibenzylamine converted cleanly to the imine. Of interest, the primary amine benzylamine is oxidized completely to benzonitrile. Several monoruthenium complexes were also evaluated for catalysis, but their reaction yields were significantly lower, supporting an intact diruthenium catalyst. 

Metal Catalysis. Aqueous solutions of amine oxides are unstable in the presence of mild steel and thermal decomposition to secondary amines and aldehydes under acidic conditions occurs (24,25). The reaction proceeds by a free-radical mechanism (26). The decomposition is also cataly2ed by V(III) and Cu(I). 

LI. On the basis of the evidence of trans-nitrosation and on the apparent specific catalysis by hydrochloric acid, a mechanism first proposed by Houben85 has become generally accepted 8 86,87. This involves a reversible de-nitrosation forming the secondary amine and nitrosyl chloride followed by C-nitrosation in ... 

Some of the most important evidence for the two-step mechanism comes from studies of base catalysis, in this regard, reactions involving primary and secondary amines have played a central role1-5. The initially formed cx-adduct, 1, is zwitterionic and contains an acidic proton, which can be removed by a base which may be the nucleophile itself. Conversion of 1 to products can then occur via the uncatalysed k2 pathway or via the base-catalysed hl pathway. The influence of Brpnsted base catalysis, the experimental observation of 1,1- and 1,3-cr-adducts, the sensitivity of the system to medium effects, are some experimental evidence of the mechanism depicted in equation 1. 

A kinetic study in 50% aqueous DMSO has shown that the first step in the three-step mechanism (Scheme 24) proposed for the 5NV reaction between para-substituted (methylthio)benzylidene Meldrum s acids (61) and four aliphatic primary amines is rate determining.101 The evidence supporting this mechanism is that the reactions are second order kinetically and show no base catalysis. A value of /Wc = 0.32 for the reaction with primary amines is smaller than the /9nuc = 0.41 found for the reaction with the less reactive secondary amines, indicating that N-Ca bond formation is more... 

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

During the last two decades, our group has smdied solvent effects on the process development in different molecular solvents (aprotic and protic, polar and non-polar) or in their binary mixtures, correlating the kinetic data of this reaction with empirical solvent parameters (E, n, a and 3) through Linear Free Energy Relationship s - LFER s - simple and multiparametric equations. The principal S Ar reactions studied comprise l-halo-2,4-dinitrobenzene or l-halo-2,6-dinitrobenzene as substrates and primary and secondary amines as nucleophiles. For the 1-fluoro-dinitrobenzenes derivatives, the reaction can exhibit base catalysis, which is normally solvent dependent. In general, solvent effects were related to reaction rates, mechanisms and catalysis. These studies were extented employing ILs as reaction media. 

The surprising inertness of the glycosylamines to mutarotation by a base-catalyzed mechanism arises from the small tendency of an amino nitrogen-atom to release a proton. At high alkalinities, the base-catalyzed reaction takes place to a small degree with glycosylamines of primary and secondary amines.277 With those of tertiary amines, there is no proton to be released, and the mutarotation reaction must take place by acid catalysis (see Fig. 16). The high sensitivity of the... 

In addition, to demonstrate the reaction principle for a wider range of applications including in particular asymmetric catalysis, future efforts will be directed toward the utilization of the chemical characteristics of the system in synthetic procedures. The carbonic acid equilibria (Scheme 1) provide many opportunities to interact directly with substrates, products, or catalytically active intermediates as, for example, demonstrated in Scheme 2. Up to now, the main focus has been to avoid detrimental interference of such processes in the reactions under scrutiny. As our imderstanding of the mechanisms and catalytic cycles in this medium increases, it should, however, become more and more possible to take advantage of the CO2/H2O reactivity similarly to the interaction of SCCO2 with secondary amines [47, 48],... 

With respect to the covalent activation in conjugate additions, the catalyst, usually a primary or a secondary amine, can reversibly form a chiral enamine [ 11 ] to activate the nucleophile (D, Fig. 2.2) or a chiral iminium ion [12] to activate the acceptor (E, Fig. 2.2). The detection of enamine intermediates in asymmetric oiganocatalysis has been for a long time the missing piece of evidence for the commonly accepted mechanism of enamine catalysis. This gap has been recently solved with the first detection and structnral characterization of enamine intermediates in proUne-cata-lyzed aldol reactions by real-time NMR spectroscopy [13] and the direct observation of an enamine intermediate in the crystal strnctnre of an aldolase antibody [14]. 

Kinetic studies have been reported for the reactions of some 5-nitro-2-(4-nitrophenoxy)-3-X-thiophenes (10) with aniline and 4-methoxyaniline in methanol, which yield the corresponding 2-anilino derivatives. Base catalysis was interpreted by the SB-GA (specific base-general acid) mechanism. The reactions of 5-bromothiophene-2-carboxaldehyde (11) with secondary amines in water have been shown to produce the corresponding 5-aminated derivatives by the SnAt mechanism. ... 

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