Helmi Neuvonen

Correlation analysis of the 13C chemical shifts of substituted benzaldehyde 2‐aminobenzoylhydrazones. Study of the propagation of substituent effects along a heteroatomic chain

The 13C chemical shifts of eight series of para- or meta-substituted benzaldehyde 2-aminobenzoylhydrazones possessing both amide and imine functionalities were measured. The 13C chemical shifts were used to study the transmission of electronic substituent effects along the heteroaromatic side-chain of the substituted aromatic ring. In addition to the CN bond, the benzoylhydrazones possess in their side-chain polarizable CO and phenyl π-units. The benzylidenic ring-substituent chemical shifts were analysed by the dual substituent parameter approach to separate the inductive and resonance effects. The negative ρI and ρR values observed (i.e. reverse substituent effects) indicate a significant π-polarization of the CN bond. The highly negative ρR values, especially those in the case of meta substitution, suggest a contribution from a marked secondary field-transmitted resonance effect. The results are compared with those obtained for other hydrazones or imines. Variation of the electron-withdrawing ability of the N2 substituent is seen to have a systematic effect on the ρI values. Reverse substituent effects are also observed at the C-1″ site of the 2-aminobenzoyl ring while C-4″ shifts show normal behaviour, consistent with the general concept of the π-polarization that each π-unit of the side-chain is polarized largely as a localized system. Accordingly, the π-polarization effect is seen efficiently to propagate also along a heteroaromatic chain. On the other hand, the CO sites exhibit normal, although fairly slight, dependence on the benzylidenic substituent indicating an insignificant role of π-polarization at that site. The effects of the solvent, CDCl3vs. DMSO-d6, on the ρI and ρR values are also considered.

Correlation analysis of carbonyl carbon 13C NMR chemical shifts, IR absorption frequencies and rate coefficients of nucleophilic acyl substitutions. A novel explanation for the substituent dependence of reactivity

Rate coefficients of nucleophilic acyl substitutions, carboxylate carbon 13C NMR chemical shift values and ν(CO) frequencies of several series of aryl and acyl substituted aryl acetates or alkyl benzoates have been investigated. An increasing electron-withdrawal by the acyl or aryl substituents results in higher reaction rates, upfield 13C NMR chemical shifts and higher frequencies of the CO stretching. Good correlations are observed for the log kversus δC(CO) plots. The increase of the reaction rate with increased electron density at the CO carbon (as proved by 13C NMR shifts) contradicts the previous concept of increased electrophilicity of the carbonyl carbon by electron-withdrawing substituents. The rate increase is now attributed to the decrease of the ester ground state resonance stabilization caused by electron-withdrawing substituents. The use of log kversus δC(CO) correlations is presented as a practical method to evaluate rate coefficients especially for compounds for which Hammett type correlations cannot be used.

Investigation of the applicability of cis-urocanic acid as a model for the catalytic Asp–His dyad in the active site of serine proteases based on 1H NMR hydrogen bonding studies and spectroscopic pKa measurements

The intramolecular hydrogen bond of cis-urocanic acid, (Z)-3-(1H-imidazol-4-yl)prop-2-enoic acid (cis-UCA) in DMSO has been evaluated by the 1H NMR chemical shift approach to assess the suitability of cis-UCA as a model for the Asp–His dyad in the active site of serine proteases. Both the acidic OH proton and the C2 proton of the imidazole ring of cis-UCA resonate at exceptionally low field, at ca. 17.4 and 8.2 ppm, respectively, indicating a strong N–H–O type intramolecular hydrogen bond. The nucleophilic reactivity of cis-UCA toward the acyl carbon of 4-nitrophenyl chloroacetate has been compared with that of the trans-isomer and other imidazole derivatives with the aid of kinetic studies. The non-linear kinetic behaviour observed for the reaction of cis-UCA is attributed to complex formation with the reacting acyl derivative and cis-UCA. pKa determinations of imidazole derivatives in DMSO have also been performed and a value of 3.2 has been observed for cis-UCA.