Inversion, of amines

We conclude this section with a discussion of inversion of amines of the type NR.jR.2R375>76). In general this process is too rapid to be studied except in special circumstances 100). Nevertheless, Saunders and Yamada 101 were able to determine the very high rate of inversion of dibenzylmethylamine (Fig. 50) (k = 2x 10s sec-1 at 25 °C) by the elegant trick of partially neutralizing the amine with hydrochloric acid. Since the hydrochloride cannot invert, the benzylic protons in it are diastereotopic and hence anisochronous. Only the small amount of free amine in equilibrium with the salt at a given pH (the measurements were carried out on the acid side) inverts at the rate indicated and it can be easily shown i01) that kobs. = k [amine]/[salt + amine] where kobs. is the observed rate of site exchange of the diastereotopic protons at... 

Table 1.4. Energy barrier to inversion of amines and phosphines Compound a...

BONDINGAND STRUCTURE OF AMINES Nitrogen Inversion of Amines... 

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

Ring inversions of 1H- and 4//-azepines between their two stable boat forms have been studied extensively by HNMR spectroscopy.37,38-40-76 82,85 A coalescence temperature of — 55 7 C and a AG value for ring inversion of 42.7 kJ mol have been determined for the two conformers 10 A and 10 B of A-phenyl-3//-azepin-2-amine.82... 

The NC of an amine is an important functional property to consider with high-alkalinity feed waters. The NC is inversely proportional to the MW of the amine in question, so amines with the lowest MW (such as ammonia and ME A) have the highest NC. Also, the NC for any class of amine tends to be proportional to the number of amine groups on the molecule. 

In recent studies, we found that primary and secondary amines, alone or somehow faster in the presence of the soft Lewis acid Ag+ (refs. 7-9) substitute the bromine in (S)-2-bromopropanamides, in an organic solvent, at room temperature, and yield N-alkyl-, and N,N -dialky 1-aminopropanamides, with inversion of configuration and high enantiomeric excess. Conversely, in the presence of silver oxide (Ag20), much faster reactions occur with retention of configuration, giving... 

Fig. 2. Components of Li enthalpies of complexation with methylamines. Successive steps indicate the effect on energy of interaction between Li and the amine of inclusion of additional components of the binding energy. The diagram shows that the permanent dipoles on amines (the charge on the nitrogen of the isolated amine) favor ammonia over trimethylamine complexation, but that polarizability and inductive effects (shift of negative charge onto the nitrogen in the complex) cause a massive turnaround in favor of complexation with trimethylamine rather than ammonia. Of particular importance is the near inversion of order caused by the addition of repulsive van der Waals terms. Modified after Ref. (9).

Spectrum 6.19 Slow inversion of a protonated tertiary amine nitrogen. 

Diazotisation of the potentially explosive 2-chloro-4,6-dinitroaniline in the third batch of a new process (at a higher than usual concentration in 40% nitrosylsulfuric acid) led to a violent explosion soon after the temperature had been increased to 50°C. Subsequent DSC work showed that the temperature at which thermal decomposition of the diazonium sulfate solution or suspension sets in is inversely proportional to the concentration of amine, falling from 160°C at 0.3 mmol/g to 80°C at 2 mmol/g. Thermal stability of 17 other diazonium derivatives was similarly investigated. 

Mechanisms involving axial coordination of the optically active amine have also been invoked, and crystal structure data on RCo(DMG)2B complexes, where R is alkyl or (R)-l-(methoxycarbonyl)ethyl, and B is (R )-a-methylbenzylamine, were obtained (316, 317). Because deuteration of the (R)-methoxycarbonyl complex gave (5)-methylpropionate-2-d, it was concluded that Co—C bond cleavage occurred with inversion of configuration at the carbon (317). It would be useful to know the mechanistic details of this step, which could involve attack by D+, DCo(III), or coordinated D, as well as D2, for it is an unusual, if not unique, observation [contrast with the usual retention mechanism outlined in Eq. (39)]. 

In contrast to the amines, inversion of configuration for phosphines is generally negligibly slow at ambient temperature. This property has made it possible for chiral phosphines to be highly useful as ligands in transition metal-catalyzed asymmetric syntheses. 

Based on nucleophilic addition, racemic allenyl sulfones were partially resolved by reaction with a deficiency of optically active primary or secondary amines [243]. The reversible nucleophilic addition of tertiary amines or phosphanes to acceptor-substituted allenes can lead to the inversion of the configuration of chiral allenes. For example, an optically active diester 177 with achiral groups R can undergo a racemization (Scheme 7.29). A 4 5 mixture of (M)- and (P)-177 with R = (-)-l-menthyl, obtained through synthesis of the allene from dimenthyl 1,3-acetonedicar-boxylate (cf. Scheme 7.18) [159], furnishes (M)-177 in high diastereomeric purity in 90% yield after repeated crystallization from pentane in the presence of catalytic amounts of triethylamine [158], Another example of a highly elegant epimerization of an optically active allene based on reversible nucleophilic addition was published by Marshall and Liao, who were successful in the transformation 179 — 180 [35], Recently, Lu et al. published a very informative review on the reactions of electron-deficient allenes under phosphane catalysis [244]. 

Dynamic kinetic resolution enables the limit of 50 % theoretical yield of kinetic resolution to be overcome. The application of lipase-catalyzed enzymatic resolution with in situ thiyl radical-mediated racemization enables the dynamic kinetic resolution of non-benzylic amines to be obtained. This protocol leads to (/f)-amides with high enantioselectivities. It can be applied either to the conversion of racemic mixtures or to the inversion of (5)-enantiomers. 

At first glance this inversion of the monomer ratio seems to be logical and simple, but it is not. In the first reaction step, as described in Fig. 1, the advantage of the chemoselectivity of the anhydride reacting with the secondary amine is used to obtain AB2 monomers. If an excess of anhydride is used, this selectivity is lost and not only amides but also esters are formed. From the synthesis of... 

In cyclic amines rigidity of the ring and a small angle between the C-N bonds characteristically result in a relatively high energy barrier to inversion of configuration at the nitrogen atom. The effect is most marked for aziridine derivatives, for which the kinetics of inversion processes are conveniently studied by variable-temperature NMR... 

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