What Do Ab Initio Calculations Predict for the Structure of Lithiated Azaenolates of Peptides?

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Abstract
Structures and conformations of the azaenolate lithium salts of amides (formamide, acetamide, and N‐methylacetamide) and of the dipeptide model N‐formylalaninamide were investigated by means of ab initio MO theory. Four possible structures of the lithiated C‐enolates of acetamide were also included in the study. All structures were calculated at the HF/6‐31+G(d) and MP2(fc)/6‐31 + G(d)/HF/6‐31 + G(d) levels; the lithiated azaenolates of formamide were also investigated at higher theoretical levels (up to MP4(fc)/6‐311 + G(d,p)/MP2(fc)/6‐311 + G(d,p)). For the lithiated azaenolates of all amides investigated, the most stable structure contains a four‐membered ring in which the lithium ion is complexed by the oxygen and nitrogen atoms; the substituents attached to the carbon and nitrogen atoms of the azaenolate are in a cis arrangement. The lithiated azaenolates of acetamide are predicted to be more stable than the corresponding C‐enolates. To simulate solvation, calculations on complexes of the lithiated azaenolates of formamide with up to three molecules dimethyl ether were also performed, and all azaenolates of amides were also reoptimized by ab initio reaction‐field calculations. Both solvation models reduce the preference for lithium‐chelated cis structures. The Ramachandran maps of the dilithiated bis(azaenolate) of N‐formylalaninamide (having cis or trans arrangements of the azaenolate substituents) were scanned by MNDO calculations for conformational accessible regions. Thirteen stable structures were subsequently optimized at the HF/6‐31 + G(d) ab initio level. The global minimum resembles a peptide in C7 conformation, but other conformations, not known for peptides, are close in energy. The structures of dimers of the lithiated azaenolates of N‐methylacetamide and of glycinaldehyde were also calculated. The NMR chemical shielding of carbon, nitrogen, and oxygen atoms in all structures were predicted ab initio by using the gauge‐including atomic orbital (GIAO) method.