Base-Promoted C-C Bond Activation Enables Radical Allylation with Homoallylic Alcohols.

The Cα-Cß 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. C-radical addition to the double bond of the title reagents and subsequent base-promoted homolytic Cα-Cß 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.

Mechanisms of Alkyl and Aryl Thiol Addition to N-Methylmaleimide.

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 ßnucRS-= 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 ßnucArS- = 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.

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers.

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.

Rapid Ni, Zn, and Cu ion-promoted alcoholysis of N,N-bis(2-picolyl)- and N,N-bis((1H-benzimidazol-2-yl)methyl)-p-nitrobenzamides in methanol and ethanol.

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.

Comparison of Cu(II)-promoted leaving group stabilization of the cleavage of a homologous set of phosphate mono-, di-, and triesters in water, methanol, and ethanol.

The cleavage of a set of phosphate mono-, di-, and triesters having a Cu(II)-complexed 2-phenanthrolyl group at the ortho-position of a departing phenoxide was studied in water and ethanol. Experimentally observed pH/rate profiles, solvent deuterium kinetic isotope effects, and activation parameters are compared with those obtained in methanol. The pH/rate profile in each solvent exhibits an extended plateau due to solvent attack on forms designated as [Cu(II):1b/c](0) for the monoester, [Cu(II):2b](+), for the diester, and [Cu(II):3a](2+) for the triester. The solvent dkie values (k(H)/k(D)) for the three complexes are 0.91, 0.95, and 0.83 for decomposition of [Cu(II):1b/c](0) in water (W), methanol (M), and ethanol (E), 1.22, 1.09, and 1.29 for [Cu(II):2b](+) in W, M, and E, and 1.94, 2.2, and 1.96 for [Cu(II):3a](2+) in W, M, and E. Near unit, or slightly inverse values for the monoester are taken as evidence for little involvement of solvent in a highly dissociative TS for P-OAr cleavage, with slightly higher solvent dkie values for the diester signifying the onset of some solvent participation in assisting the nucleophilic displacement. The larger primary dkie for the triester gives evidence for a solvent-assisted delivery of ROH in the cleavage through a more associative mechanism. Activation parameters for each substrate in the solvents are compared, indicating that the transition from methanol to ethanol for each substrate involves a near cancellation of the ΔΔH(‡) and -TΔΔS(‡) values (25 °C) so that the respective rates in both solvents are very similar. The transition from alcohol to water produces variable effects, with ΔΔH(‡) and -TΔΔS(‡) values canceling for cleavage of the triester and being additive for the mono and diester, explaining their 100-500 rate reduction in passing from methanol to water. The rate enhancing effects of the Cu(II)-promoted leaving group assistance in all three solvents are substantial and estimated at 10(12)-10(15) for the monoester, 10(12)-10(14) for the diester, and 10(5) for the triester relative to their background reactions.

Trifunctional metal ion-catalyzed solvolysis: Cu(II)-promoted methanolysis of N,N-bis(2-picolyl) benzamides involves unusual Lewis acid activation of substrate, delivery of coordinated nucleophile, powerful assistance of the leaving group departure.

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.

Quinone methide dimers lacking labile hydrogen atoms are surprisingly excellent radical-trapping antioxidants.

Hydrogen atom transfer (HAT) is the mechanism by which the vast majority of radical-trapping antioxidants (RTAs), such as hindered phenols, inhibit autoxidation. As such, at least one weak O-H bond is the key structural feature which underlies the reactivity of phenolic RTAs. We recently observed that quinone methide dimers (QMDs) synthesized from hindered phenols are significantly more reactive RTAs than the phenols themselves despite lacking O-H bonds. Herein we describe our efforts to elucidate the mechanism by which they inhibit autoxidation. Four possible reaction paths were considered: (1) HAT from the C-H bonds on the carbon atoms which link the quinone methide moieties; (2) tautomerization or hydration of the quinone methide(s) in situ followed by HAT from the resultant phenolic O-H; (3) direct addition of peroxyl radicals to the quinone methide(s), and (4) homolysis of the weak central C-C bond in the QMD followed by combination of the resultant persistent phenoxyl radicals with peroxyl radicals. The insensitivity of the reactivity of the QMDs to substituent effects, solvent effects and a lack of kinetic isotope effects rule out the HAT reactions (mechanisms 1 and 2). Simple (monomeric) quinone methides, to which peroxyl radicals add, were found to be ca. 100-fold less reactive than the QMDs, ruling out mechanism 3. These facts, combined with the poor RTA activity we observe for a QMD with a stronger central C-C bond, support mechanism 4. The lack of solvent effects on the RTA activity of QMDs suggests that they may find application as additives to materials which contain H-bonding accepting moieties that can dramatically suppress the reactivity of conventional RTAs, such as phenols. This reactivity does not extend to biological membranes owing to the increased microviscosity of the phospholipid bilayer, which suppresses QMD dissociation in favour of recombination. Interestingly, the simple QMs were found to be very good RTAs in phospholipid bilayers - besting even the most potent form of vitamin E.