Cyclopropylcarbinyl Radical Research Articles

Radical Stabilization Energies for Enzyme Engineering: Tackling the Substrate Scope of the Radical Enzyme QueE.

Experimental assessment of catalytic reaction mechanisms and profiles of radical enzymes can be severely challenging due to the reactive nature of the intermediates and sensitivity of cofactors such as iron-sulfur clusters. Here, we present an enzyme-directed computational methodology for the assessment of thermodynamic reaction profiles and screening for radical stabilization energies (RSEs) for the assessment of catalytic turnovers in radical enzymes. We have applied this new screening method to the radical S-adenosylmethione enzyme 7-carboxy-7-deazaguanine synthase (QueE), following a detailed molecular dynamics (MD) analysis that clarifies the role of both specific enzyme residues and bound Mg2+, Ca2+, or Na+. The MD simulations provided the basis for a statistical approach to sample different conformational outcomes. RSE calculation at the M06-2X/6-31+G* level of theory provided the most computationally cost-effective assessment of enzyme-based energies, facilitated by an initial triage using semiempirical methods. The impact of intermolecular interactions on RSE was clearly established, and application to the assessment of potential alternative substrates (focusing on radical clock type rearrangements) proposes a selection of carbon-substituted analogues that would react to afford cyclopropylcarbinyl radical intermediates as candidates for catalytic turnover by QueE.

A vinylcyclobutane substrate designed as a cyclopropylcarbinyl radical probe

Appending a spirocyclopropane linkage to bicyclo[3.2.0]hept-2-ene is achieved by selective kinetic cyclopropanation of 6-methylenebicyclo[3.2.0]hept-2-ene. The resultant vinylcyclobutane undergoes [1,3] migration as the dominant thermal process. A minor cyclopropylcarbinyl (CPC) rearrangement product clearly implicates a diradical transition structure. The presence and absence of other potential thermal products have enabled us to construct a detailed mechanistic proposal to account for all viable dynamic processes.

Kinetic isotope effects calculated with the instanton method

The ring-opening reaction of the cyclopropylcarbinyl radical proceeds via heavy-atom tunneling at low temperature. We used instanton theory to calculate tunneling rates and kinetic isotope effects with on-the-fly calculation of energies by density functional theory (B3LYP). The accuracy was verified by explicitly correlated coupled-cluster calculations (UCCSD(T)-F12). At cryogenic temperatures, we found protium/deuterium KIEs up to 13 and inverse KIEs down to 0.2. We also studied an intramolecular tautomerization reaction. A simple and computationally efficient method is proposed to calculate KIEs with the instanton method: the instanton path is assumed to be independent of the atomic masses. This results in surprisingly good estimates of the KIEs for the cyclopropylcarbinyl radical and for the secondary KIEs of the tautomerization. Challenges and capabilities of the instanton method for calculating KIEs are discussed.

Effects of geminal methyl groups on the tunnelling rates in the ring opening of cyclopropylcarbinyl radical at cryogenic temperature

CVT + SCT calculations on the rate of tunnelling at 20 K in the ring opening of cyclopropylcarbinyl radical, substituted with geminal methyl groups at a ring carbon (1b), have been performed. The calculations predict that, contrary to expectations based on the effect of mass on the rate of tunnelling, the geminal methyl substituents in 1b should make the rate of ring opening to 1,1-dimethyl-3-butenyl radical (2b) 10(4) times faster than the rate of ring opening of unsubstituted cyclopropylcarbinyl radical (1a) to 3-butenyl radical (2a) and almost 10(6) times faster than the rate of ring opening of 1b to 2,2-dimethyl-3-butenyl radical (2c). The reasons for these unexpected findings are discussed.

ChemInform Abstract: The Photochemical Generation of α-Sulfur-Substituted Cyclopropylcarbinyl Radicals and Their Utilization as a Mechanistic Probe for Electron Transfer in the Peroxide-Sulfide Reaction.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Calibration of a New Horologery of Fast Radical “Clocks”. Ring-Opening Rates for Ring- and α-Alkyl-Substituted Cyclopropylcarbinyl Radicals and for the Bicyclo(2.1.0)pent-2-yl Radical.

ChemInform Abstract: Calibration of a New Horologery of Fast Radical “Clocks”. Ring-Opening Rates for Ring- and α-Alkyl-Substituted Cyclopropylcarbinyl Radicals and for the Bicyclo(2.1.0)pent-2-yl Radical.

Experimental Evidence for Heavy-Atom Tunneling in the Ring-Opening of Cyclopropylcarbinyl Radical from Intramolecular 12C/13C Kinetic Isotope Effects

The intramolecular (13)C kinetic isotope effects for the ring-opening of cyclopropylcarbinyl radical were determined over a broad temperature range. The observed isotope effects are unprecedentedly large, ranging from 1.062 at 80 degrees C to 1.163 at -100 degrees C. Semiclassical calculations employing canonical variational transition-state theory drastically underpredict the observed isotope effects, but the predicted isotope effects including tunneling by a small-curvature tunneling model match well with experiment. These results and a curvature in the Arrhenius plot of the isotope effects support the recently predicted importance of heavy-atom tunneling in cyclopropylcarbinyl ring-opening.

ChemInform Abstract: Kinetics of Cyclopropylcarbinyl Radical Ring Openings Measured Directly by Laser Flash Photolysis.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Free Radical Mediated Ring Expansion Reactions: Endocyclic Cleavage of Cyclopropylcarbinyl Radicals.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Theoretical studies of the effects of substituents on the ring opening reactions for the cyclopropylcarbinyl radical

DFT (U)B3LYP/6-31G(d,p), (U)B3LYP/6-31+G(d,p), and (U)B3LYP/6-311+G(d,p) calculations were carried out to investigate the ring opening reactions of the cyclopropylcarbinyl radical (leading to the 3-butenyl radical) and its mono-substituted analogues containing the methyl, ethyl, propyl, isopropyl, isobutyl, fluorine, chlorine, bromine, hydroxyl, methoxy, cyanogen, nitryl, vinyl, and phenyl substituents on the ring (leading to the pseudo-secondary and primary radicals, respectively). The enthalpies of activation, rate constants, and reaction enthalpies for all ring opening reactions were calculated. The predicted enthalpy of activation, rate constant, and reaction enthalpy of the cyclopropylcarbinyl radical ring opening reaction are in excellent agreement with the corresponding experimental values. For the alkyl (methyl, ethyl, propyl, isopropyl, and isobutyl) substitutions, steric effects are found to be the dominating factor to affect the ring opening reactions, while for the rest substitutions, the stereoelectronic effects play the most important roles. Our calculations indicate that the cyanogen, nitryl, vinyl, and phenyl substituents, which contain π bonds, have much larger effects on the ring opening reactions than the other substituents.

Two Approaches to Diverting the Course of a Free-Radical Cyclization: Application of Cyclopropylcarbinyl Radical Fragmentations and Allenes as Radical Acceptors

Free radical cyclization of 4 and 7 gave the expected cyclization-reduction products (5 and 8) along with considerable amounts of products derived from a cyclization-atom transfer-secondary cyclization process (6 and 9). Two approaches to avoiding these unexpected products were explored. Use of a cyclopropylcarbinyl fragmentation avoided the secondary cyclization reaction (25 or 43 --> 26 or 44), whereas use of an allene as a radical acceptor avoided the atom-transfer reaction altogether (49 --> 52).

Calculations Predict a Large Inverse H/D Kinetic Isotope Effect on the Rate of Tunneling in the Ring Opening of Cyclopropylcarbinyl Radical

B3LYP/6-31G* calculations have been performed, to compute the kinetic isotope effects (KIEs) on the rate of ring opening of cyclopropylcarbinyl radical (1) to 3-buten-1-yl radical (2) at 20 K by tunneling. The most striking result of our small curvature tunneling calculations is the prediction of a 2.7-fold increase in the rate of reaction by substitution of D(2) for H(2) at C(1). The origin of this very surprising, inverse KIE on the rate of tunneling is discussed.

Calculations Predict Rapid Tunneling by Carbon from the Vibrational Ground State in the Ring Opening of Cyclopropylcarbinyl Radical at Cryogenic Temperatures

B3LYP/6-31G(d) calculations have been performed on the ring opening of cyclopropylcarbinyl radical 1 to 3-buten-1-yl radical 2. The dynamics of the reaction have been computed with canonical variational transition state theory (CVT), both with and without inclusion of small-curvature tunneling (SCT). The CVT + SCT calculations predict that 1 should undergo rapid and temperature-independent ring opening to 2 at cryogenic temperatures, by tunneling from the lowest vibrational level of 1.

A Novel Method of Remotely Triggering a Cyclopropyl Carbinyl to Homo-allyl Radical Fragmentation Process

A series of model compounds were prepared in order to investigate the conditions that would favour the formation of a cyclopropyl carbinyl radical via a 1,5 hydrogen atom translocation process. The models varied in the degree of unsaturation adjacent to the cyclopropyl carbinyl position and it was found that the 1,5 hydrogen atom radical translocation process was favoured only when alternative cyclisation pathways were not possible.

Mechanism of Oxygenation of 2,6-Di-tert-butylphenol Derivative

The base-catalyzed oxygenation of phenol or naphthol derivatives has been of interest in both biological and synthetic system. In general, when phenoxide anions 1 are exposed to triplet molecular oxygen, the corresponding epoxy alcohols 7 are formed in nearly quantitative yield. Possible reaction pathway for the oxidation process is proposed as shown in Scheme 1. Reaction of the phenoxide anions 1 and molecular oxygen results in the peroxides 4, which then undergo intramolecular conjugate addition to form the dioxetane enolate anions 5. Finally, dioxetane ring opening by nucleophilic displacement yields the epoxy alcohols 6. However, the reaction pathway of molecular oxygen and phenoxide anions 1 to form the peroxides 4 might be unfavorable because the singlet phenolate anions 1 cannot react in a single step with triplet molecular oxygen to yield the singlet products. To overcome the spin-forbidden rule, two possible mechanisms of base-catalyzed oxygenation of phenol derivatives have been proposed. One is a charge transfer mechanism (pathway 1), where the phenolate anion 1 interacts with πorbital of molecular oxygen to afford a triplet charge transfer complex 2. The complex then experiences intersystem crossing i.e., one of unpaired electrons undergoes the spin inversion from the triplet charge transfer complex to the singlet complex, giving a singlet oxygen. Alternative pathway is an electron transfer mechanism (pathway 2). The phenoxide anions 1 react with molecular oxygen to give the phenoxyl radicals 3 and superoxide by one-electron transfer. The phenoxyl radicals 3 then trap superoxide to yield the peroxy anions 4. Here we report theoretical and experimental investigations of the possible intermediate involved in the base-catalyzed oxygenation of phenol derivative. Previously, we synthesized the cyclopropyl derivative 8 of 2,6-di-tert-butylphenol to distinguish phenoxide anion 11 from the phenoxy radical 12 in the course of autoxidation because rearrangement of the cyclopropyl radical to homoallylcarbinyl radical was thought to be effective in the shortlived radical trap. When a solution of potassium phenolate 9 in tetrahydrofuran was stirred under an atmosphere of oxygen at room temperature, the corresponding epoxy alcohol 10 was formed and no ring-opened product 14 was detected in the reaction mixtures. Therefore, we suggested a charge transfer mechanism describing the action of basecatalyzed oxygenation of phenols. Although it has been suggested that α-cyclopropylbenzyl radicals undergo fairly rapid rearrangement, little is known about the stabilities of cyclopropylcarbinyl radical 12 with the radical-stabilizing group and homoallylcarbinyl radical 13. Interestingly, in this study, our semi-empirical calculation using AM1 indicated that the Gibbs free energies of radical 12 and radical 13 are −4266.39 kcal/mol and −4265.70 kcal/ mol, respectively, showing that the free energy change of rearrangement is endothermic by 0.69 kcal/mol. This result suggests that ring-opening of 12 can not be only reversible but that equilibrium may favor the ring closed form, and the radical probe 8 might give an unclear guide to charge transfer mechanism in the previous work. To examine whether singlet oxygen was really produced via energy transfer, we then carried out the oxygenation reaction of potassium phenolate 9 in the presence of 1,4-diazbicyclo[2,2,2]octane(Dabco), which has been known to inhibit singlet oxygen reactions but has little effect on free radical reactions. However, addition of Dabco did not have any influence, indicating that singlet oxygen was not a primary oxidizing species in the base-catalyzed autoxidation. Regarding electron transfer from the phenoxide anion to molecular oxygen (pathway 2), it has been proposed that superoxide ion does not couple with 2,6-di-tert-butylphenoxy radicals but reduces radicals to give the corresponding phenoxide anions, and mechanism involving for the base-

Acid-, Base-, and Lewis-Acid-Catalyzed Heterolysis of Methoxide from an α-Hydroxy-β-methoxy Radical: Models for Reactions Catalyzed by Coenzyme B12-Dependent Diol Dehydratase

[Reaction: see text].A model for glycol radicals was employed in laser flash photolysis kinetic studies of catalysis of the fragmentation of a methoxy group adjacent to an alpha-hydroxy radical center. Photolysis of a phenylselenylmethylcyclopropane precursor gave a cyclopropylcarbinyl radical that rapidly ring opened to the target alpha-hydroxy-beta-methoxy radical (3). Heterolysis of the methoxy group in 3 gave an enolyl radical (4a) or an enol ether radical cation (4b), depending upon pH. Radicals 4 contain a 2,2-diphenylcyclopropane reporter group, and they rapidly opened to give UV-observable diphenylalkyl radicals as the final products. No heterolysis was observed for radical 3 under neutral conditions. In basic aqueous acetonitrile solutions, specific base catalysis of the heterolysis was observed; the pK(a) of radical 3 was determined to be 12.5 from kinetic titration plots, and the ketyl radical formed by deprotonation of 3 eliminated methoxide with a rate constant of 5 x 10(7) s(-1). In the presence of carboxylic acids in acetonitrile solutions, radical 3 eliminated methanol in a general acid-catalyzed reaction, and rate constants for protonation of the methoxy group in 3 by several acids were measured. Radical 3 also reacted by fragmentation of methoxide in Lewis-acid-catalyzed heterolysis reactions; ZnBr2, Sc(OTf)3, and BF3 were found to be efficient catalysts. Catalytic rate constants for the heterolysis reactions were in the range of 3 x 10(4) to 2 x 10(6) s(-1). The Lewis-acid-catalyzed heterolysis reactions are fast enough for kinetic competence in coenzyme B12 dependent enzyme-catalyzed reactions of glycols, and Lewis-acid-catalyzed cleavages of beta-ethers in radicals might be applied in synthetic reactions.

A Combined Theoretical and Experimental Study of Efficient and Fast Titanocene-Catalyzed3-exoCyclizations

The mechanism of titanocene mediated 3-exo cyclizations was investigated by a combined theoretical and experimental study. A gradient corrected density functional theory (DFT) method has been scaled against titanocene dichloride, the parent butenyl radical, and in bond dissociation energy (BDE) calculations. The BP86 method using density fitting, and a basis set of triple-zeta quality emerged as a highly reliable tool for studying titanocene mediated radical reactions. The computational results revealed important kinetic and thermodynamic features of cyclopropane formation. Surprisingly, the beta-titanoxy radicals, the first intermediates of our investigations, were demonstrated to possess essentially the same thermodynamic stabilization as the corresponding alkyl radicals by comparison of the calculated BDEs. In contrast to suggestions for samarium mediated reactions, the cyclization was shown to be thermodynamically favorable in agreement with earlier kinetic studies. It was established that stereoselectivity of the cyclization is governed by the stability of the intermediates and thus the trans disubstituted products are formed preferentially. The observed ratios of products are in good to excellent agreement with the DFT results. By a combination of computational and experimental results, it was also shown that for the completion of the overall cyclopropane formation the efficiency of the trapping of the cyclopropylcarbinyl radicals is decisive.

An Efficient Photoinduced Iodoperfluoroalkylation of Carbon—Carbon Unsaturated Compounds with Perfluoroalkyl Iodides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cyclopropylcarbinyl Radicals as Three‐Carbon Insertion Units: Easy Synthesis of C‐15 Macrocyclic Ketones by Three‐Carbon Ring Expansion.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An efficient photoinduced iodoperfluoroalkylation of carbon-carbon unsaturated compounds with perfluoroalkyl iodides.

Dependent on the selection of the light sources employed, the photoinduced iodoperfluoroalkylation of a variety of unsaturated compounds takes place efficiently via a radical mechanism. Upon irradiation with a xenon lamp through Pyrex (hnu >300 nm), terminal alkenes (R-CH=CH2) and alkynes (R-C triple bond CH) undergo iodoperfluoroalkylation with perfluoroalkyl iodides (RF-I) regioselectively, providing R-CH(I)-CH2-RF and R-C(I)=CH-RF, respectively. In the case of terminal allenes (R-CH=C=CH2), the photoinduced iodoperfluoroalkylation occurs selectively at the terminal double bond, giving the corresponding beta-perfluoroalkylated vinylic iodides (R-CH=C(I)-CH2-RF) in good yields. The photoinitiated reaction of vinylcyclopropanes (c-C3H5-C(R)=CH2) with RF-I proceeds via the rearrangement of cyclopropylcarbinyl radical intermediates to the homoallylic radical intermediates, and the corresponding 1,5-iodoperfluoroalkylated products (I-(CH2)2CH=C(R)-CH2-RF) are obtained in high yields. Isocyanides (R-NC), as C-N unsaturated compounds, also undergo the xenon-lamp-irradiated iodoperfluoroalkylation to provide the corresponding 1,1-adducts (R-N=C(I)-RF) in good yields. Furthermore, the present photoinitiation procedure can be applied to the iodotrifluoromethylation of unsaturated compounds, when the xenon-lamp-irradiated reactions are conducted under the refluxing conditions of excess CF3-I.