The methanolyses of Cu(II) complexes of a series of N,N-bis(2-picolyl) benzamides (4a-g) bearing substituents X on the aromatic ring were studied under (s)(s)pH-controlled conditions at 25 °C. The active form of the complexes at neutral (s)(s)pH has a stoichiometry of 4:Cu(II):((-)OCH(3))(HOCH(3)) and decomposes unimolecularly with a rate constant k(x). A Hammett plot of log(k(x)) vs σ(x) values has a ρ(x) of 0.80 ± 0.05. Solvent deuterium kinetic isotope effects of 1.12 and 1.20 were determined for decomposition of the 4-nitro and 4-methoxy derivatives, 4b:Cu(II):((-)OCH(3))(HOCH(3)) and 4g:Cu(II):((-)OCH(3))(HOCH(3)), in the plateau region of the (s)(s)pH/log(k(x)) profiles in both CH(3)OH and CH(3)OD. Activation parameters for decomposition of these complexes are ΔH(++) = 19.1 and 21.3 kcal mol(-1) respectively and ΔS(++) = -5.1 and -2 cal K(-1) mol(-1). Density functional theory (DFT) calculations for the reactions of the Cu(II):((-)OCH(3))(HOCH(3)) complexes of 4a,b and g (4a, X = 3,5-dinitro) were conducted to probe the relative transition state energies and geometries of the different states. The experimental and computational data support a mechanism where the metal ion is coordinated to the N,N-bis(2-picolyl) amide unit and positioned so that it permits delivery of a coordinated Cu(II):((-)OCH(3)) nucleophile to the C═O in the rate-limiting transition state (TS) of the reaction. This proceeds to a tetrahedral intermediate INT, occupying a shallow minimum on the free energy surface with the Cu(II) coordinated to both the methoxide and the amidic N. Breakdown of INT is a virtually barrierless process, involving a Cu(II)-assisted departure of the bis(2-picolyl)amide anion. The analysis of the data points to a trifunctional role for the metal ion in the solvolysis mechanism where it activates intramolecular nucleophilic attack on the C═O group by coordination to an amidic N in the first step of the reaction and subsequently assists leaving group departure in the second step. The catalysis is very large; compared with the second order rate constant for methoxide attack on 4b, the computed reaction of CH3O(-) and 4b:Cu(II):(HOCH(3))(2) is accelerated by roughly 2.0 × 10(16) times.

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of p-unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radical-trapping antioxidants; more so than the phenols from which they are derived – or transformed to – despite the fact that they do not possess a labile H-atom for transfer to the peroxyl radicals that propagate autoxidation.

The C α −C β bond in homoallylic alcohols can be activated under basic conditions, qualifying these nonstrained acyclic systems as radical allylation reagents. This reactivity is exemplified by photoinitiated (with visible light and/or blue LEDs) allylation of perfluoroalkyl and alkyl radicals generated from perfluoroalkyl iodides and alkylpyridinium salts, respectively, with homoallylic alcohols. Cradical addition to the double bond of the title reagents and subsequent base-promoted homolytic C α −C β cleavage leads to the formation of the corresponding allylated products along with ketyl radicals that act as single electron reductants to sustain the chain reactions. Substrate scope is documented and the role of base in the C−C bond activation is studied by computation.

The methanolysis and ethanolysis of the Ni(II), Zn(II), and Cu(II) complexes of N,N-bis(2-picolyl)-p-nitrobenzamide (1) and N,N-bis((1H-benzimidazol-2-yl)methyl)-p-nitrobenzamide (2) were studied under pH-controlled conditions at 25 °C. Details of the mechanism were obtained from plots of the kobs values for the reaction under pseudo-first-order conditions as a function of [M2+]. Such plots give saturation kinetics for the Cu(II)-promoted reactions of 1 and 2 in both solvents, the Zn(II)-promoted reaction of 1 in methanol, and the Zn(II)- and Ni(II)-promoted reactions of 2 in methanol and ethanol. Logs of the maximal observed rate constants obtained from the latter plots, (kobs(max)), when plotted versus s(s)pH, are curved downward only for the Cu(II) complexes of 1 and 2 in both solvents and the Zn(II) complex of 1 in methanol. Despite differences in the metal-binding abilities and pKa values for formation of the active form, there is a common reaction mechanism, with the active form being 1:M(II):(–OR) and 2:M(II):(–OR), where M(II):(–OR) is the metal-bound alkoxide. The acceleration provided by the metal ion is substantial, being 10(14)–10(19) relative to the k2(¯OMe) value for the alkoxide-promoted alcoholysis of the uncomplexed amide.

A mechanistic study was undertaken to elucidate the reaction pathways for thiol addition to N-methylmaleimide in water. We used linear free energy relationships, solvent kinetic isotope effects (SKIEs), activation parameters, and ionic strength effects to probe the nature of the rate-limiting transition states. Calculations were also employed and assisted in illuminating three possible mechanistic pathways: (1) stepwise addition with rate-limiting nucleophilic attack, (2) stepwise addition with rate-limiting proton transfer, and (3) concerted addition with nucleophilic attack and proton transfer occurring concurrently. Alkyl thiolate addition exhibits β= 0.4, small negative Δ S values, prominent ionic strength effects, and no evidence of general acid catalysis, consistent with pathway 1. Aryl thiolate addition exhibited β = 1.0, large negative Δ S values, normal primary SKIEs, general acid catalysis, and negligible sensitivity to ionic strength, consistent with pathways 2 and 3. The experimental and computational data depict an energy surface where ground state effects, namely the energy of the alkyl/aryl thiolate, play a major role in shaping the governing pathway. Application of these findings to bioconjugation chemistry is also discussed.