Amines amine inversion

In terms of cost, the effectiveness of the catalytic cycle in the ring closure makes this process economical in palladium. The first three steps in the reaction sequence -- ring opening of an epoxide by a Grignard reagent, converison of an alcohol to an amine with inversion, and sulfonamide formation from the amine — are all standard synthetic processes. 

Since the rate was independent of acidity even over the range where H0 and pH differ, and the concentration of free amine is inversely proportional to the acidity function it follows that the rate of substitution is proportional to h0. If the substitution rate was proportional to [H30+] then a decrease in rate by a factor of 17 should be observed on changing [H+] from 0.05 to 6.0. This was not observed and the discrepancy is not a salt effect since chloride ion had no effect. Thus the rate of proton transfer from the medium depends on the acidity function, yet the mechanism of the reaction (confirmed by the isotope effect studies) is A-SE2, so that again correlation of rate with acidity function is not a satisfactory criterion of the A-l mechanism. 

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. 

Diels-Alder Reactions The organocatalytic Diels-Alder reaction of a,P-unsaturated carbonyl compounds can be performed either via iminium (see Section 11.3) or enamine catalysis. The first highly selective enamine-promoted cycloaddition reaction was reported by Jprgensen and coworkers, who developed an amine-catalyzed inverse-electron-demand hetero-Diels-Alder (HDA) reaction (Scheme ll.lOa). ... 

Unlike tertiary amines the inversion barriers of simple tertiary phosphines of the type PRMePh are high enough to allow isolation, if not distillation of pure enantiomers.185 Determinations of... 

With ammonia, inversion of this type occurs about 4 x ]010 times per second at room temperature, which corresponds to the planar state being less stable than the pyramidal state by about 6 kcal mole-1. With aliphatic tertiary amines, the inversion rate is more on the order of 103 to 105 times per second. Such rates of inversion are much too great to permit resolution of an amine into its enantiomers by presently available techniques. 

Two mechanistically plausible scenarios for nucleophilic attack on the q benzyl palladium species seem feasible. Formation of the C N bond could occur either via external attack of the amine through inversion of configuration at the carbon stereocenter, or alternatively the amine could coordinate to palladium followed by an internal attack on the q benzyl ligand. Mechanistic investigations [15] using stoi chiometric amounts ofthe enantio and diastereomerically pure q benzyl palladium complex [ (R) Tol BINAP [q 1 (2 naphthyl)ethyl Pd](OTf) (8) revealed that the re action with aniline produced predominantly (R) N1 (2 naphthyl)ethylaniline R) 9), consistent with external nucleophilic attack (Scheme 11.3) [15]. However, it was noted that the catalytic reaction of [ (1 ) Tol BINAP Pd(OTf)2] with vinyl arenes and amines produced preferentially the opposite enantiomeric (S) amine hydroamination... 

If one of the four groups attached to nitrogen is a lone pair, the enantiomers cannot be separated because they interconvert rapidly at room temperature. This is called amine inversion (Section 21.2). One way to picture amine inversion is to compare it to an umbrella that turns inside out in a windstorm. 

Although the activation enthalpy of this process AG = 70 kJ mol i.e. substantially greater than with a secondary aliphatic amine, inversion occurs so rapidly at room temperature that the diastereo-isomers are not separable. However, in the case of l-chloro-2-methylaziridine, where AG = 112 kJ mol , the mixture of stereoisomers can be separated. 

S )-0-Ethyl O-phenyl pho.sphorochloridothioate reacts with amines with inversion of configuration at phosphorus the resultant phosphorothioic amides undergo acid hydrolysis... 

KHMDS was shown to be as effective as LHMDS in the boron-assisted displacement of secondary chloride which led to the corresponding protected amine with inversion of configuration (eq 26). The chemoselective displacement of the chloride is greatly facilitated by the a-boro substituent, which is known to cause a rate acceleration on the attack of nucleophiles of approximately two orders of magnitude relative to the primary halide. ... 

In contrast with amines, the inversion at the phosphorus atom in phosphanes is much more hindered and, therefore, the influence of the lone pair of electrons at the phosphorus atom becomes more readily apparent if the substituents prefer a particular orientation. This can be enforced by using bulky substituents (Scheme 27). The effect has first been observed for /( P, C) in aminophosphanes, where the J values are large and positive for a sy/j-orientation and small and negative for anti-orientation of the respective N-C bonds and the assumed orientation of the lone electron pair at the phosphorus atom. The analogous stereochemical dependence is observed for V( P,N, Si) as shown for the A-silylaminophosphanes 135 and 136 (Scheme 27). ... 

Because amines undergo fluxional inversion, nitrogen is not considered to he chiral and amines are treated as equilibrating mirror images (racemates). In some polycyclic amines, fluxional inversion is impossible, and nitrogen can be chiral, with the lone electron pair considered as the fourth group. 

The most important structural feature of amines comes from the presence of the pair of nonbonding electrons acting as the fourth substituent on the pyramid. In alkanes, where there are four substituents, there is nothing more to consider once the pyramid is described. In amines there is, because the pyramid can undergo an umbrella flip, amine inversion, forming a new, mirror-image pyramid (Rg. 6.39). 

FIGURE 6.39 Amine inversion interconverts enantiomeric amines. 

FIGURE 6.40 The transition state for amine inversion is planar. 

---