It is still a challenge to predict a compound's reactivity from its ground-state electronic nature although Bader-type topological analyses of the electron density (ED) and electron localizability indicator (ELI) give detailed and useful information on electron concentration and electron-pair localization, respectively. Both ED and ELI can be obtained from theoretical calculations as well as high-resolution X-ray diffraction experiments. Besides ED and ELI descriptors, the delocalization index is used here; it is likewise derived from theoretical calculations as well as from experimental X-ray results, but in the latter case, demonstrated here for the first time. We investigate α,β-unsaturated carbonyl and hydrazone compounds because resonance exhibited by these compounds in the electronic ground-state determines their reactive behavior. The degree of resonance as well as the reactivity contrast are quantified with the electronic descriptors. Moreover, competitive mesomeric substituent effects are studied using the two biologically important compounds acrolein and acrylamide. The reactivity differences predicted from the analyses are in line with the known reactivity of these compounds in organic synthesis. Hence, the capability of the ED and ELI for rationalizing and predicting different and competing substituent effects with respect to reactivity is demonstrated.
N,N-Dimethylhydrazones of propenal-and 2-methylpropenal and their derivatives and homologues (vinylogous azaenamines) were allowed to react with N,N-dimethylformiminium chloride in moisture-free dimethylformamide to yield singly, doubly, and even triply aminomethylated products. They can be easily separated and characterized as crystalline hydrochlorides. The reaction takes place at the w-position of the p-system. This is a consequence of the conjugative interaction of the electron-donating aminohydrazone group with the double bond system in analogy to the enamines. The formation of dialkylhydrazones from unsaturated aldehydes thus causes the umpolung of the formerly electrophilic d 3 -building blocks into a nucleophile. Depending on the reaction conditions and confirmed by crystal structures and 2D NMR experiments, control can be exerted over the degree of substitution: Up to trisubstituted products were obtained for the 2-methylpropenal derivative. The hydrochlorides can be easily deprotonated to yield the free aminohydrazone bases. The back-conversion of the aminohydrazones into the corresponding amino aldehydes is possible under acidic conditions. The isoelectronic exchange of C1 in enamines I 3 by nitrogen formally leads to aldehyde hydrazones III (Scheme 1). Such hydrazones can be formally regarded as aza-enamines. Some time ago, we could demonstrate that besides this formal connection, also real relations exist in the reactivities of both structural classes. Both react with electrophiles E + , the enamines at C2 to yield II and the aldehyde hydrazones at the azomethine C-atom giving rise to IV. Consequently, the azomethine carbon corresponds to the enamine C2 carbon atom. Both owe this property to the conjugative interaction between the electron-donating dialkylated nitrogen atom and the carbon-carbon and carbon-nitrogen double bonds in the sense of mesomeric structures I¢ and III¢. The aldehyde hydrazones are N,Ndialkylated, for example, as in the pyrrolidino, piperidino, or dimethylamino derivatives, because they proved to be the most effective electron donors in enamine chemistry. 3 Examples for this behavior of aldehyde N,N-dialkylhydrazones are the acylation with the Vilsmeier reagent 4a-d,f and trifluoroacetic anhydride, 5a,b the carboxylation with sulfonyl isocyanates, 4b,e,6a-d as well as the alkylation with electrophilic olefins (Scheme 1). 7a-cThe reactions occur contrary to the normal polarity of the imino structural element as expressed in III¢¢; thus, such hydrazones proved to react as umpoled d 1 -nucleophilic aldehyde derivatives. Moreover, they are neutral acyl anion equivalents and thus differ from these strongly alkaline reagents. 8a-c This aza-enamine principle is also applicable to vinylogous aldehyde hydrazones. Consequently the dimethylhydrazones of the a,b-unsaturated aldehydes V are attacked by electrophiles at the vinylogous C3-position leading to VI (Scheme 2). This represents an umpolung of the Michael acceptor reactivity. Therefore, these neutral d 3 -nucleophilic building block...
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