Computational studies of nucleophilic substitution at carbonyl carbon: the S(N)2 mechanism versus the tetrahedral intermediate in organic synthesis.
A theoretical study specifically addresses the question of whether nucleophilic addition to the carbonyl groups of acid chlorides, esters, and anhydrides involves an addition-elimination pathway or proceeds by a concerted S(N)2-like mechanism in the absence of the generally assumed tetrahedral intermediate. Density functional calculations [B3LYP/6-31+G(d,p)] establish that chloride ion exchange reactions with both formyl and acetyl chloride proceed by a pi attack on the C=O bond. No discernible tetrahedral intermediate typical of an addition-elimination pathway was found in either case. While a tetrahedral intermediate does exist for the addition of fluoride ion to (Cl)(2)C=O, halide exchange of LiCl with both ClFC=O and (Cl)(2)C=O also proceeds by a concerted S(N)2-like pathway. The formation of a tetrahedral intermediate from the addition of methanol to acetyl chloride is slightly exothermic (4.4 kcal/mol). The ion-dipole complex of methanol weakly bonded to the carbonyl carbon of protonated acetyl chloride is stabilized by 13.8 kcal/mol but does not collapse to a tetrahedral intermediate. When four CH(3)OH molecules are H-bonded to protonated acetyl chloride, a tetrahedral intermediate is not completely formed and this solvated complex more closely resembles the precursor to an S(N)1-type ionization of Cl(-). With six H-bonding methanol molecules, a methanol adds to the carbonyl carbon and a proton relay occurs with formation of a tetrahedral-like structure that immediately loses chloride ion in an S(N)1-like solvolysis. These results corroborate earlier suggestions (Bentley et al. J. Org. Chem. 1996, 61, 7927) that the methanolysis of acetyl chloride does not proceed through the generally assumed addition-elimination pathway with a discrete tetrahedral intermediate but is consistent with ionization of Cl(-). The reaction of methoxide ion with methyl acetate proceeds via a multiple-well energy surface and involves the intermediacy of an asymmetrical species with differing C-OMe bond lengths. Models of synthetic applications of acyl transfer reactions involving anhydrides that form N-acyloxazolidinones also proceed by a concerted S(N)2-type pathway even with the carboxylate leaving group. Concerted transition states were observed for the reactions of each enantiomer of a 1,3-diphenylcycloprop-2-ene carboxylic anhydride by S-3-lithio-4-phenyloxazolidinone. Despite close structural similarities between the diastereomeric transition states, the relative energies correlated closely with the experimental results.
Fox
Joseph M
JM
Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19803, USA.
Dmitrenko
Olga
O
Liao
Lian-An
LA
Bach
Robert D
RD
D002244:Carbon / Q000737:chemistry*; D003198:Computer Simulation; D003521:Cyclopropanes / Q000737:chemistry; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009930:Organic Chemicals / Q000138:chemical synthesis*; D023303:Oxazolidinones / Q000138:chemical synthesis
D003521:Cyclopropanes; D009930:Organic Chemicals; D023303:Oxazolidinones; D002244:Carbon