Theses Doctoral

I. The Reaction of Carboxylic/Thiocarboxylic Acids with Isonitriles II. Ruthenium Hydride Ring Opening of an Azetidinium Cation

Polisar, Jason Gary

The mechanism of the reaction of benzoic acid with cyclohexyl isonitrile leading to N-cyclohexyl-N-formylbenzamide has been studied quantitatively. The reaction is first order in each reagent and has the activation parameters delta H = 16.9(5) kcal mol-1 and delta S = 26(1) cal mol-1K-1 in toluene. There is a dramatic solvent effect: hydrogen bond accepting solvents retard the rate of the reaction by deactivation of the carboxylic acid. A plot of log(rate constant) vs beta (hydrogen bond acceptor basicity of the solvent) is a straight line with a substantial negative slope, implying that the reaction is retarded by hydrogen bonding to the solvent but not affected significantly by other solvent properties. It is speculated that the related Passerini reaction is affected in a similar matter, although quantitative data for this reaction are sparse in the literature. Variation of concentrations allows control over the product distribution in the reaction of carboxylic acids and isonitriles. With low concentrations of the acid, the N-formylamide is obtained in good yield because low concentrations suppress the nucleophilic interception of the intermediate formimidate carboxylate mixed anhydrides (FCMAs), which leads to the undesired anhydride and formamide. With arylacetic acids, N-formylamides (the products of a unimolecular process) are obtained with low concentrations of the reactants and high reaction temperatures. At low temperatures and high concentrations, captodative alkenes (the products of a bimolecular process) are obtained instead. In contrast to the high temperatures needed for RNC + RCO2H -- N-formylamide, thioacids react at ambient temperature with isonitriles to give N-thioformylamides. Transient intermediates can be observed during the reaction. Two thio-analogues of the FCMA are suggested by NMR spectral evidence. However, the structure of a third intermediate (which forms more slowly than the other two) remains unknown. Several mechanisms for this reaction are kinetically indistinguishable because the three intermediates interchange more rapidly than the product-forming step (which is irreversible). The solvent effect observed with carboxylic acids is not observed with thioacids, presumably because of the weaker hydrogen bond donating strength of the S-H in the thioacid. The mechanism and temperature dependence of the hydride ring opening of a phenyl azetidinium cation has been studied. The reaction with CpRu(dppm)H (dppm = bis(diphenylphosphino)methane) is first order in both the hydride and the azetidinium. Extrapolation of the rate constant to -64 °C (the temperature at which an analogous aziridinium ring opening was previously examined) shows that aziridiniums undergo hydride ring opening 10^6 - 10^7 times faster. This result implies that aziridiniums are much more electrophilic than azetidiniums, although these two rings have a strain energy difference of only 2.1 kcal mol-1. Nucleophilic attack on azetidiniums generally occurs at the less substituted position in accords with an SN2 mechanism. However, with a phenyl substituent, hydride transfer by half-sandwich ruthenium complexes occurs preferentially at the more substituted position (ca. 5:1) giving the straight-chain amine. More reactive hydrides (borohydrides, LiAlH4) erode this preference. As is the case with electrophilicity, there is a significant difference in the reduction potential between a phenyl aziridinium (Epc = -0.93 V vs FcH+/FcH) and a phenyl azetidinium (Epc = -1.43 V). While the phenyl aziridinium has been previously shown to undergo single electron reduction by Cp*Ru(dppf)H (E1/2 = -0.63 V, dppf = 1,1'-bis(diphenylphosphino)ferrocene), the phenyl azetidinium failed to react with the same reagent. The azetidinium did react with decamethylcobaltocene (E1/2 = -1.94 V) giving the expected straight-chain ring-opened amine among a mixture of products; none of the branched amine was detected.


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More About This Work

Academic Units
Thesis Advisors
Norton, Jack R.
Ph.D., Columbia University
Published Here
June 7, 2013