Inversion at nitrogen

Trigonal pyramidal molecules are chiral if the central atom bears three different groups If one is to resolve substances of this type however the pyramidal inversion that mterconverts enantiomers must be slow at room temperature Pyramidal inversion at nitrogen is so fast that attempts to resolve chiral amines fail because of their rapid racemization... 

Although unsynunetrically substituted amines are chiral, the configuration is not stable because of rapid inversion at nitrogen. The activation energy for pyramidal inversion at phosphorus is much higher than at nitrogen, and many optically active phosphines have been prepared. The barrier to inversion is usually in the range of 30-3S kcal/mol so that enantiomerically pure phosphines are stable at room temperature but racemize by inversion at elevated tempeiatuies. Asymmetrically substituted tetracoordinate phosphorus compounds such as phosphonium salts and phosphine oxides are also chiral. Scheme 2.1 includes some examples of chiral phosphorus compounds. 

A similar situation occurs in trivalent phosphorus compounds, or phosphines. It turns out, though, that inversion at phosphorus is substantially slower than Inversion at nitrogen, so stable chiral phosphines can be isolated. (R)- and (5)-metbylpropylphenylphosphine, for example, are configurationally stable for several hours at 100 °C. We ll see the Importance of phosphine chirality in Section 26.7 in connection with the synthesis of chiral amino adds. 

Evidence for slow inversion at nitrogen in the compound (106) and its tetrachloro analogue has been obtained 142>. The adduct of tetra-fluorobenzyne with cyclopentadiene has been obtained but of rather more interest is the isolation of the isomeric adducts (108) and (109) from the reaction of tetrafluorobenzyne with nickelocene 143>. No adducts were obtained from attempted reactions with ferrocene 144 80). 

The barrier to inversion at nitrogen in A-heteroatom-substituted hydroxamic esters should be greater than that found for hydroxamic esters or simple amides. However, it is likely to be substantially reduced in anomeric amides relative to amines since the planar transition state in which nitrogen is sp hybridized, can benefit from jr-overlap with the carbonyl (Figure 3b) and this has been verified experimenfally Rudchenko has measured an inversion barrier for A,A-dialkoxyureas af AG = 9-11 kcalmoH and fhose of acyclic dialkoxyamines fypicaUy af AG = 20-22 kcalmoH ... 

In tolnene-rfg, below 217 K, the benzyl aromatic signal resolved into two and the ben-zylic protons became diastereotopic. The exchange process, which was characterized by 217 = 246 s and AG = 10.2 kcalmoU, is a complex process involving both rotation aronnd the O—N bond and inversion at nitrogen, bnt since barriers to the former process are small the barrier best reflects that for rotation away from the anomeric conformation (Fignre 13). The amide isomerization barrier is even lower and both energies are in accordance with theoretical calcnlations (10.7 and 7.7 kcalmoG, respectively, for A—O rotation and amide isomerism in A-chloro-A-methoxyformamide) . 

The barrier to inversion at nitrogen was 3.5 kcalmol" at the B3LYP/6-31G level in line with that of the A-chloro model, 2b (2.5 kcalmol". Section III.B.l). 

When the amine nitrogen is incorporated in a small ring, as in azacyclo-propanes, 1, the rate of inversion at nitrogen is markedly slower than in open-chain amines. In fact, with some oxazacyclopropanes, such as 2, inversion... 

A detailed investigation of such isomers and their rates of interconversion has been carried out on Cp2Fe2(CO)4 jr(CNMe)Jt (x = 2, 3) (185). In both cases it was shown that the expected isomers do occur and can be observed at low temperature. The barriers to inversion at nitrogen were relatively low and the step itself was not rate determining. 

To explore the full potential of what is sometimes called dynamic NMR 54>, i.e. NMR studies involving site and ligand exchange, is beyond the scope of this chapter and the reader is referred to numerous reviews 40 41 54 75 82). Only a few examples of the application of this technique can be given here, e.g. in the study of ring inversion, rotation about single bonds and inversion at nitrogen. 

PE spectroscopy has been used to identify gas phase conformations of 1,3,4-oxadiazolidines. The ring adopts a half-chair conformation (80CB221). Inversion at nitrogen in 3,4-disubstituted 1,3,4-oxadiazolidines has been studied using variable temperature NMR spectroscopy <75JCS(P2)1191). 

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