Mechanism for the gas‐phase reaction between OH and 3‐methylfuran: A theoretical study

The mechanism for the OH + 3‐methylfuran reaction has been studied via ab initio calculations to investigate various reaction pathways on the doublet potential energy surface. Optimizations of the reactants, products, intermediates, and transition structures are conducted using the MP2 level of theory with the 6‐311G(d,p) basis set. The single‐point electronic energy of each optimized geometry is refined with G3MP2 and G3MP2B3 calculations. The theoretical study suggests that the OH + 3‐methylfuran reaction is dominated by the formation of HC(O)CH?C(CH₃)CHOH (P7) and CH(OH)CH?C(CH₃)C(O)H (P9), formed from two low‐lying adducts, IM1 and IM2. The direct hydrogen abstraction pathways and the S_N2 reaction may play a minor or negligible role in the overall reaction of OH with 3‐methylfuran. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

Theoretical studies of spin state‐specific [2 + 2] and [5 + 2] photocycloaddition reactions of n‐(1‐penten‐5‐yl)maleimide

N‐alkenyl maleimides are found to exhibit spin state‐specific chemoselectivities for [2 + 2] and [5 + 2] photocycloadditions; but, reaction mechanism is still unclear. In this work, we have used high‐level electronic structure methods (DFT, CASSCF, and CASPT2) to explore [2 + 2] and [5 + 2] photocycloaddition reaction paths of an N‐alkenyl maleimide in the S₁ and T₁ states as well as relevant photophysical processes. It is found that in the S₁ state [5 + 2] photocycloaddition reaction is barrierless and thus overwhelmingly dominant; [2 + 2] photocycloaddition reaction is unimportant because of its large barrier. On the contrary, in the T₁ state [2 + 2] photocycloaddition reaction is much more favorable than [5 + 2] photocyclo‐addition reaction. Mechanistically, both S₁ [5 + 2] and T₁ [2 + 2] photocycloaddition reactions occur in a stepwise, nonadiabatic means. In the S₁ [5 + 2] reaction, the secondary C atom of the ethenyl moiety first attacks the N atom of the maleimide moiety forming an S₁ intermediate, which then decays to the S₀ state as a result of an S₁ → S₀ internal conversion. In the T₁ [2 + 2] reaction, the terminal C atom of the ethenyl moiety first attacks the C atom of the maleimide moiety, followed by a T₁ → S₀ intersystem crossing process to the S₀ state. In the S₀ state, the second C C bond is formed. Our present computational results not only rationalize available experiments but also provide new mechanistic insights. © 2017 Wiley Periodicals, Inc.     

Regioselective Mono‐ and Dialkylation of [6,6]‐open C60(CF2): Synthetic and Kinetic Aspects

Alkylation of homofullerene [6,6]‐C₆₀(CF₂)^2? dianion with the set of alkyl halides, RX, was established to demonstrate an effect of RX nature on the conversion, product composition, and regioselectivity. The respective C₆₀(CF₂)RH, C₆₀(CF₂)R₂ and C₆₀(CF₂)R’R’’ compounds were obtained in the reaction with sterically unhindered RX, isolated by HPLC and unequivocally characterized. The kinetic studies evidenced S_N2 mechanism for both alkylation steps, yielding mono‐ and dialkylated C₆₀(CF₂), respectively, and indicated the negative charge localization at the bridgehead carbon atoms as well as a steric hindrance of the CF₂ moiety likely to be a key factors for the S_N2 reaction mechanism and observed regioselectivity. The significant difference in the rate constants of the first and the second steps is attributed to the different activation barriers predicted by DFT calculations which makes possible to develop synthetic methods for the regioselective preparation of monoalkylated C₆₀(CF₂)RH and heterodialkylated C₆₀(CF₂)R’R’’ derivatives.     

Theoretical study of DABCO-based ionic liquid: synthesis and reaction mechanism

Quaternary ammonium salt obtained from the Menshutkin reaction between DABCO and benzyl chloride has been used in the synthesis of a novel Bronsted acidic ionic liquid (IL), namely 1-benzyl-4-(sulfobutyl)-diaza-bicyclo-octane hydrogen sulfate. The reaction of DABCO with benzyl chloride is a crucial step in the synthesis of this IL. Density functional theory calculations at B3LYP/6-31G(d,p) level have been employed to investigate the mechanism of Menshutkin reaction by calculating the energy barriers through possible transition states i.e., five-membered ring transition state and S_N2 transition state in gas phase and in diethyl ether as a solvent. It was found that while DABCO reacts with benzyl chloride through the well-known S_N2 transition state mechanism, the corresponding reaction with chlorodiphenylmethane can proceed through both S_N2 and five-membered ring transition state mechanism. However, S_N2 transition state mechanism is still the strongly preferred one out of the two possible mechanisms. The electronic structure analysis shows that solvent effects and enhanced resonance stabilization may play a decisive role in guiding the reaction pathway.     

Facile Synthesis of N‐Carboranyl Amines through an ortho‐Carboryne Intermediate

The efficient o‐carboryne precursor 1‐Li‐2‐OTf‐o‐C₂B₁₀H₁₀ reacts with lithium amides at room temperature to give a series of N‐carboranyl amines in moderate to high isolated yields. This reaction is compatible with a broad substrate scope from primary to secondary, alkyl to aryl amines. The reaction mechanism is also proposed on the basis of experimental results and DFT calculations. This represents the first general and efficient method for the synthesis of 1‐NR¹R²‐o‐carboranes.     

Reactions of fluoroalkanesulfonyl azides with diethyl phosphite,a new method for the synthesis of N‐fluoroalkane‐sulfonylphosphoramidates

N‐Fluoroalkanesulfonylphosphoramidates, R₁SO₂NHP(O)‐(OEt)₂, have been prepared by a one‐step reaction of fluoroalkanesulfonyl azides (R₁SO₂N₃) with diethyl phosphite at room temperature. The reaction mechanism was also discussed and a favored mechanism was suggested.     

A Novel 2H‐Azirin‐3‐amine as a Dipeptide (Aib‐Hyp) Synthon

The synthesis of methyl (2S,4R)‐4‐(benzyloxy)‐N‐(2,2‐dimethyl‐2H‐azirin‐3‐yl)prolinate ( 10 ), a novel 2H‐azirin‐3‐amine (`3‐amino‐2H‐azirine'), is described (Scheme 1). The reaction of methyl (2S,4R)‐N‐(2‐methylpropanoyl)‐4‐(benzyloxy)prolinate ( 7 ) with Lawesson reagent gave methyl (2S,4R)‐4‐(benzyloxy)‐N‐[2‐(methylthio)propanoyl]prolinate ( 8 ) and consecutive treatment with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ led to 10 . The use of 10 as a building block of the dipeptide Aib‐Hyp (Aib=2‐aminoisobutyric acid, Hyp=(2S,4R)‐4‐hydroxyproline) is demonstrated by the syntheses of several model peptides (Scheme 2 and Table). The benzyl protecting group of the 4‐OH function in Hyp in the model peptides has been removed in good yields.     

Mechanism and Selectivity of the Oxidative Ring Contraction of Cyclic α‐Formyl Ketones

The oxidative contraction of α‐formal ketone to form continuous all carbon chiral centers promoted by H₂O₂ is widely used in natural product total synthesis. Typically, using this transformation, chiral cyclic ketones are obtained as the major products and ring‐opening products as the minor products. Herein, DFT calculations have been used to investigate the detailed reaction mechanism and chemoselectivity. In addition, with the widely accepted mechanism of H₂O₂‐promoted transformation, our systematic investigation with various explicit‐solvent‐model calculations for the first time shows that H₂O and H₂O₂ are comparable at catalyzing the rate‐determining step of this reaction, which emphasis the importance of solvent effect in such transformations. It is found that both the less ring‐constrain and a later transition state in an exothermic reaction account for the origin why the reaction favors ring‐contraction pathway rather than ring‐opening one. By a comprehensive analysis for the substituted groups, it has been disclosed that the steric effects of the substituted groups on R² and R³ contribute to the selectivity with larger steric hindrance favoring the chiral cyclic products. Moreover, the electronic effects on R¹ but not R³ affect the selectivity with electron‐donating groups leading to the cyclic products. Based on our calculations, some predictions for higher selectivity have been made.     

Free‐radical 4‐nitrophenylation of thieno[2,3‐b]pyridine. Part 3: Consideration of mechanistic and selectivity factors involved in the substitution process

A 1:1 geometrically oriented encounter complex between thieno[2,3‐b]pyridine (1) and 4‐nitrophenyldia‐zoacetate (2) is proposed to account for the dominant formation (ca. 64%) of the 2‐isomer in the mixture of 4‐nitrophenyl‐l isomers obtained previously. A mechanism involving one‐electron transfer from 1 to 2 plus fragmentation of 2· into 4‐nitrophenyl free radical, N₂, and acetate ion is invoked. Formation of other isomers is discussed. It is noted that there is a close correlation between orientational rules plus mechanisms of reaction for numerous free‐radical substitutions (S_R) with S_N reactions of alkyllithiums on furan, thiophene, N‐alkylpyrroles, pyridine, and their condensed aromatic molecules, including 1, as substrates. Also isomeric selectivities for S_E, S_N, and S_R substitutions into 1 were shown to be qualitatively consistent with one another. While S_E reactions occur largely at position 3 and then at 2, S_N and S_R reactions occur either at 2 or 6. Selectivity for positions 4 or 5 is small or zero.     

Theoretical studies of the hydrolysis reaction of 5′‐AMP

The hydrolysis reaction mechanisms of the phosphate group, with and without an adenosine connected to it, have been theoretically investigated at the B3LYP/6‐31G** level. It is found that each reaction is single‐channel with a two‐step process. When H₂O approaches the phosphate group, a penta‐coordinated intermediate (IM1‐a) is formed first, followed by the H transfer reaction with P? O broken at the same time. This process belongs to the addition‐elimination process, similar to the carboxylate. In addition, the solvent effect has been studied by the polarizable continuum model (PCM). Our present calculations have rationalized and verified all the possible reaction channels. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2006     

The diastereoisomers methyl 5‐(S)‐[2‐(R)/(S)‐methoxycarbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methylphenyl)‐4,5‐dihydropyrazole‐3‐carboxylate

The title diastereoisomers, methyl 5‐(S)‐[2‐(S)‐methoxy­carbonyl)‐2,3,4,5‐tetra­hydro­pyrrol‐1‐yl­carbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate and methyl 5‐(S)‐[2‐(R)‐methoxycarbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxylate, both C₁₉H₂₃N₃O₅, have been studied in two crystalline forms. The first form, methyl 5‐(S)‐[2‐(S)‐methoxy­carbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methylphenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate–methyl 5‐(S)‐[2‐(R)‐methoxy­carbonyl)‐2,3,4,5‐tetra­hydro­pyrrol‐1‐yl­carbonyl]‐1‐(4‐methylphenyl)‐4,5‐dihydropyrazole‐3‐carboxylate (1/1), 2(S),5(S)‐C₁₉H₂₃N₃O₅·2(R),5(S)‐C₁₉H₂₃N₃O₅, contains both S,S and S,R isomers, while the second, methyl 5‐(S)‐[2‐(S)‐methoxycarbonyl)‐2,3,4,5‐tetrahydro­pyrrol‐1‐ylcarbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate, 2(S),5(S)‐C₁₉H₂₃N₃O₅, is the pure S,S isomer. The S,S isomers in the two structures show very similar geometries, the maximum difference being about 15° on one torsion angle. The differences between the S,S and S,R isomers, apart from those due to the inversion of one chiral centre, are more remarkable, and are partially due to a possible rotational disorder of the 2‐­(methoxycarbonyl)tetrahydropyrrole group.     

The multieffects of DMF and DBU on the [5 + 1] benzannulation of nitroethane and α‐alkenoyl ketene‐(S,S)‐acetals: Hydrogen bonding and electrostatic interactions

A density functional theory (DFT) study was performed to elucidate the mechanism for the [5 + 1] benzannulation of nitroethane and α‐alkenoyl ketene‐(S,S)‐acetals. The calculation results are consistent with experimental findings, showing that the reaction proceeds via deprotonation of nitroethane, nucleophilic addition, intramolecular cyclization, elimination of HNO₂, and the keto‐enol tautomerization sequence. It was disclosed that N,N‐dimethylformamide (DMF) and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) act as not only solvent and nonnucleophilic base, respectively, but also catalysts in the reaction by stabilizing the transition states (TSs) and intermediates via intermolecular hydrogen bonds and electrostatic interactions. Besides, the effective orbital interaction of the reaction site in TS also contributes to the intramolecular cyclization step. The new mechanistic insights obtained by DFT calculations highlight that the hydrogen bonds and electrostatic interactions are key factors for the [5 + 1] benzannulation of nitroethane and α‐alkenoyl ketene‐(S,S)‐acetals. © 2015 Wiley Periodicals, Inc.     

Chemoselectivity as a Delineator of Cuprate Structure in Catalytic 1,4‐Addition of Diorganozinc Reagents to Michael Acceptors

Reaction of the cyclic thioacetal (RS)₂CHCHO [R=1/2×? (CH₂)₃? ] with HCCCOMe, followed by treatment with TsCl/DABCO (Ts=tosyl, DABCO=1,4‐diazabicyclo[2.2.2]octane) affords the mono‐protected 1,4‐benzoquinone dithioacetal. The reactivity of this SR‐protected 1,4‐benzoquinone has been compared with the behavior of the analogous OR‐protected acetal in copper‐catalyzed additions of ZnMe₂ by using chiral phosphoramidite ligands. The activation energy for 1,4‐methylation of the latter OR‐acetals with ZnMe₂ (>95 % ee) has been determined for two CuX₂ pre‐catalysts (X=OAc, 12.2 kcal mol^?1; X=OTf, 6.7 kcal mol^?1; Tf=triflate). The dithioacetal SR aromatizes in the presence of Cu^I/ZnMe₂ giving 1,4‐HOC₆H₄S(CH₂)₃SMe through C? S bond formation. The disparate behavior of these two very closely related substrates is in accordance with the formation of closely related cuprate intermediates that were optimized by DFT calculations, supporting the synthetic and kinetic studies and thus defining the mechanisms of both pathways.     

NO migration from N‐methyl‐N‐nitrosobenzene‐sulfonamide to 3,6‐dibromocarbazole: Concerted or stepwise reaction path?

The NO migration from N‐methyl‐N‐nitrosobenzene‐sulfonamide to 3,6‐dibromocarbazole was proposed in a recent literature to follow a stepwise reaction path. However, the present density functional theory calculations at the MP2/6–31G(d,p)//B3LYP/6–31G(d,p) level show that this reaction exclusively proceeds via a concerted mechanism involving a four‐membered ring transition state. The calculated barrier is in good agreement with the experimental finding. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Gold(I)‐catalyzed Benzylation of (Hetero)aryl Boronic Acids with (Hetero)benzyl Bromides by the Strategy of a SN2‐type Reaction

Herein, the first example of gold‐catalyzed benzylation of (hetero)aryl boronic acids with (hetero)benzyl bromides to give the corresponding cross‐coupling products in moderate to good yields is reported. The reaction proceeds through a possible intermolecular S_N2‐type reaction pathway to give a wide variety of di(hetero)arylmethanes as the desired products. An intriguing reaction mechanism has been proposed on the basis of control experiments, ³¹P‐NMR spectroscopic detection and DFT calculations.     

A QM/MM Investigation of the Catalytic Mechanism of Metal‐Ion‐Independent Core 2 β1,6‐N‐Acetylglucosaminyltransferase

β1,6‐GlcNAc‐transferase (C2GnT) is an important controlling factor of biological functions for many glycoproteins and its activity has been found to be altered in breast, colon, and lung cancer cells, in leukemia cells, in the lymhomonocytes of multiple sclerosis patients, leukocytes from diabetes patients, and in conditions causing an immune deficiency. The result of the action of C2GnT is the core 2 structure that is essential for the further elongation of the carbohydrate chains of O‐glycans. The catalytic mechanism of this metal‐ion‐independent glycosyltransferase is of paramount importance and is investigated here by using quantum mechanical (QM) (density functional theory (DFT))/molecular modeling (MM) methods with different levels of theory. The structural model of the reaction site used in this report is based on the crystal structures of C2GnT. The entire enzyme–substrate system was subdivided into two different subsystems: the QM subsystem containing 206 atoms and the MM region containing 5914 atoms. Three predefined reaction coordinates were employed to investigate the catalytic mechanism. The calculated potential energy surfaces discovered the existence of a concerted S_N2‐like mechanism. In this mechanism, a nucleophilic attack by O6 facilitated by proton transfer to the catalytic base and the separation of the leaving group all occur almost simultaneously. The transition state for the proposed reaction mechanism at the M06‐2X/6‐31G** (with diffuse functions on the O1′, O5′, O_Glu, and O6 atoms) level was located at C1? O6=1.74 Å and C1? O1=2.86 Å. The activation energy for this mechanism was estimated to be between 20 and 29 kcal mol^?1, depending on the method used. These calculations also identified a low‐barrier hydrogen bond between the nucleophile O6H and the catalytic base Glu320, and a hydrogen bond between the N‐acetamino group and the glycosidic oxygen of the donor in the TS. It is proposed that these interactions contribute to a stabilization of TS and participate in the catalytic mechanism.     

4H‐1‐Benzopyrans by a tandem SN2‐SNAr reaction

Treatment of 2‐fluoro‐5‐nitrobenzyl bromide with active methylene compounds in the presence of excess potassium carbonate in acetone leads to the formation of highly functionalized 4H‐1‐benzopyrans by a tandem S_N2‐S_NAr reaction sequence. The reaction works well with β‐keto esters, β‐keto sulfones, β‐keto phosphine oxides, β‐keto phosphonates and β‐keto nitriles. The reaction is simple to perform and affords products in 50‐92% yields.     

Enantioselective Synthesis of (−)‐(R)‐Cordiachromene and (−)‐(R)‐Dictyochromenol Utilizing Intramolecular SNAr Reaction

A simple and efficient enantioselective synthesis of chromene, (?)‐(R)‐cordiachromene ( 1 ), and (?)‐(R)‐dictyochromenol ( 2 ) has been accomplished. This convergent synthesis utilizes intramolecular S_NAr reaction for the formation of chroman ring, and Seebach's method of ‘self‐reproduction of chirality’ should establish the (R)‐configuration of the C(2) side chain as key steps.     

Solvent and substituent effects on the reaction of 2‐ and 4‐chloro‐3,5‐dinitrobenzotrifluorides with substituted anilines

The solvent effect on a nucleophilic substitution reaction of 2‐ and 4‐chloro‐3,5‐dinitrobenzotrifluoride with substituted anilines was studied in methanol, acetonitrile, and toluene at 25°C. This reaction is of second order, except 2‐chloro‐3,5‐dinitrobenzotrifluoride in toluene shows third order. The k_A values are found to be dependent on the substituent in aniline and give good Hammett correlations. The obtained ρ values are ?4.07 and ?4.62, for the reaction of anilines with 2‐chloro‐3,5‐dinitrobenzotrifluoride in methanol and acetonitrile, respectively. The ρ values for the reaction of the anilines with 4‐chloro‐3,5‐dinitrobenzotrifluoride are ?3.38, ?4.11, and ?4.34 in methanol, acetonitrile, and toluene, respectively. The reaction of the former compound with anilines in toluene shows a second order in aniline. The dependence of the reaction on the external base such as DABCO suggests a proton transfer controlling step. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 41: 777–786, 2009     

Ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylates by a tandem addition‐elimination‐SNAr reaction

The ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate ring structure, important in several drug compounds, has been prepared in two steps from ethyl 2‐(2‐fluorobenzoyl)acetate. Treatment of this β‐ketoester with N,N‐dimethylformamide dimethyl acetal gives a 97% yield of the 2‐dimethylaminomethylene derivative. Reaction of this β‐enaminone with primary amines in N,N‐dimethylformamide at 140°C for 48 h then affords the 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate esters in 60–74% yields by a tandem addition‐elimination‐S_NAr reaction. The synthesis of the starting material as well as procedural details and a mechanistic scenario are presented. J. Heterocyclic Chem., (2011).