Beyond Frontier Molecular Orbital Theory: A Systematic Electron Transfer Model (ETM) for Polar Bimolecular Organic Reactions

Polar bimolecular reactions often begin as charge-transfer complexes and may proceed with a high degree of electron transfer character. Frontier molecular orbital (FMO) theory is predicated in part on this concept. We have developed an electron transfer model (ETM) in which we <i>systematically</i> transfer one electron between reactants and then use density functional methods to model the resultant radical or radical ion intermediates. Sites of higher reactivity are revealed by a composite spin density map (SDM) of odd electron character on the electron density surface, assuming that a new two-electron bond would occur preferentially at these sites. ETM correctly predicts regio- and stereoselectivity for a broad array of reactions, including Diels–Alder, dipolar and ketene cycloadditions, Birch reduction, many types of nucleophilic additions, and electrophilic addition to aromatic rings and polyenes. Conformational analysis of radical ions is often necessary to predict reaction stereochemistry. The electronic and geometric changes due to one-electron oxidation or reduction parallel the reaction coordinate for electrophilic or nucleophilic addition, respectively. The effect is more dramatic for one-electron reduction

A Computational Model for the Dimerization of Allene

Computations at the CCSD­(T)/6-311+G­(d,p)//B3LYP/6-311+G­(d,p) level of theory support long-held beliefs that allene dimerization to 1,2-dimethylenecyclobutane proceeds through diradical intermediates rather than a concerted _π2_s + _π2_a mechanism. Two diastereomeric transition states with orthogonal and skew geometries have been located for C2–C2 dimerization of allene, with predicted barriers of 34.5 and 40.3 kcal/mol, respectively. In dimerization, the outward-facing ligands rotate in a sense opposite to the forming C–C bond. Both transition states lead to nearly orthogonal (D₂) singlet bisallyl (or tetramethyleneethane) diradical. This diradical has a barrier to planarization of 3.2 kcal/mol through a planar D_2h geometry and a barrier to methylene rotation of 14.3 kcal/mol. Bisallyl diradical closes through one of four degenerate paths by a conrotatory motion of the methylene groups with a predicted barrier of 15.7 kcal/mol. The low barrier to planarization of bisallyl, and similar barriers for methylene rotation and conrotatory closure are consistent with a stepwise dimerization process which can still maintain stereochemical elements of reactants. These computations support the observation that racemic 1,3-disubstituted allenes, with access to an orthogonal transition state which minimizes steric strain, will dimerize more readily than enantiopure materials and by a mechanism that preferentially bonds M and P enantiomers

Computational Studies on a Carbenoid Mechanism for the Doering–Moore–Skattebøl Reaction

The reaction of geminal dihalocyclopropanes with metals or alkyllithiums affords carbenoids which undergo low-temperature ring opening to allenes; this is known as the Doering–Moore–Skattebøl reaction. DFT and CCSD­(T)//DFT computations have been used to model the structure, coordination state, and ring opening of 1-bromo-1-lithiocyclopropane as a model for cyclopropylcarbenoid chemistry. Both implicit (PCM) and explicit solvation models have been applied. Carbenoid ring opening is similar to the process predicted in earlier studies on cyclopropylidene. The initial disrotatory stereochemistry becomes conrotatory en route to the allene–LiBr complex. Predissociation of the carbenoid to cyclopropylidene + LiBr is not supported by computations. DFT computations predict modestly exergonic dimerization of the carbenoid, with or without solvation, and the dimer appears to be the most likely reactive species in solution. Predicted barriers to ring opening are only modestly affected by solvation or by dimer formation, remaining in the range of 9–12 kcal/mol throughout

Dehydropericyclic Reactions: Symmetry-Controlled Routes to Strained Reactive Intermediates

The conceptual dehydrogenation of pericyclic reactions yields dehydropericyclic processes, which usually lead to strained or reactive intermediates. This is a simple scheme for inventing new chemical reactions. Computational results on two novel dehydropericyclic reactions are presented here. Conjugated enynes undergo a singlet-state photoisomerization that transposes the methylene carbon. We previously suggested excited-state closure to 1,2-cyclobutadiene followed by thermal ring opening. CCSD­(T)//DFT computations show two minima of similar energy corresponding to 1,2-cyclobutadiene, one chiral and closed shell and the second a planar diradical. The chiral structure has a low barrier to ring opening and may best explain results on enyne photoisomerization. The first examples of 1,3-diyne + yne cycloadditions to give <i>o</i>-benzynes were reported in 1997. Computations on intramolecular versions of this tridehydro (−3H₂) Diels–Alder reaction support a concerted mechanism for the parent triyne (1,3,8-nonatriyne); however, a slight electronic advantage in the concerted path may be outweighed by the difference in entropy of activation for sequential vs simultaneous formation of two new ring bonds

Phenyl Shifts in Substituted Arenes via <i>Ipso</i> Arenium Ions

The isomerization of substituted arenes through <i>ipso</i> arenium ions is an important and general molecular rearrangement that leads to interconversions of constitutional isomers. We show here that the superacid trifluoromethanesulfonic acid (TfOH), ca. 1 M in dichloroethane (DCE), provides reliable catalytic reaction conditions for these rearrangements, easily applied at ambient temperature, reflux (84 °C), or in a microwave reactor for higher temperatures. Interconversion of terphenyl isomers in TfOH/DCE at 84 °C gives an <i>ortho</i>/<i>meta</i>/<i>para</i> equilibrium ratio of 0:65:35, nearly identical to values reported earlier by Olah with catalysis by AlCl₃. For the three triphenylbenzenes, TfOH-catalyzed equilibration strongly (>95%) favors the 1,3,5-triphenyl isomer. Equilibration of the three possible tetraphenylbenzenes gives a 61:39 mixture of the 1,2,3,5- and 1,2,4,5-substituted isomers. Under the reaction conditions explored, none of these structures undergoes significant Scholl cyclization. DFT calculations with inclusion of solvation support a mechanistic scheme in which all of the phenyl migrations occur among a series of <i>ipso</i> arenium ions. In every case studied, the preferred isomers at equilibrium are those that yield highly stable cations by the most exothermic, hence least reversible 1,2-H shift

Acid-Catalyzed Skeletal Rearrangements in Arenes: Aryl versus Alkyl Ring Pirouettes in Anthracene and Phenanthrene

In 1 M triflic acid/dichloroethane, anthracene is protonated at C9, and the resulting 9-anthracenium ion is easily observed by NMR at ambient temperature. When heated as a dilute solution in triflic acid/dichloroethane, anthracene undergoes conversion to phenanthrene as the major volatile product. Minor dihydro and tetrahydro products are also observed. MALDI analysis supports the simultaneous formation of oligomers, which represent 10–60% of the product. Phenanthrene is nearly inert to the same superacid conditions. DFT and CCSD­(T)//DFT computational models were constructed for isomerization and automerization mechanisms. These reactions are believed to occur by cationic ring pirouettes which pass through spirocyclic intermediates. The direct aryl pirouette mechanism for anthracene has a predicted DFT barrier of 33.6 kcal/mol; this is too high to be consistent with experiment. The ensemble of experimental and computational models supports a multistep isomerization process, which proceeds by reduction to 1,2,3,4-tetrahydroanthracene, acid-catalyzed isomerization to 1,2,3,4-tetrahydrophenanthrene with a predicted DFT barrier of 19.7 kcal/mol, and then reoxidation to phenanthrene. By contrast, DFT computations support a direct pirouette mechanism for automerization of outer ring carbons in phenanthrene, a reaction demonstrated previously by Balaban through isotopic labeling

Scholl Cyclizations of Aryl Naphthalenes: Rearrangement Precedes Cyclization

In 1910, Scholl, Seer, and Weitzenbock reported the AlCl₃-catalyzed cyclization of 1,1′-binaphthyl to perylene. We provide evidence that this classic organic name reaction proceeds through sequential and reversible formation of 1,2′- and 2,2′-binaphthyl isomers. Acid-catalyzed isomerization of 1,1′-binaphthyl to 2,2′-binaphthyl has been noted previously. The superacid trifluoromethanesulfonic acid (TfOH), 1 M in dichloroethane, catalyzes these rearrangements, with slower cyclization to perylene. Minor cyclization products are benzo­[<i>k</i>]­fluoranthene and benzo­[<i>j</i>]­fluoranthene. At ambient temperature, the observed equilibrium ratio of 1,1′-binaphthyl, 1,2′-binaphthyl, and 2,2′-binaphthyl is <1:3:97. DFT calculations with the inclusion of solvation support a mechanistic scheme in which <i>ipso</i>-arenium ions are responsible for rearrangements; however, we cannot distinguish between arenium ion and radical cation mechanisms for the cyclization steps. Under similar reaction conditions, 1-phenylnaphthalene interconverts with 2-phenylnaphthalene, with the latter favored at equilibrium (5:95 ratio), and also converts slowly to fluoranthene. Computations again support an arenium ion mechanism for rearrangements

Biomimetic Total Synthesis of (±)-Griffipavixanthone via a Cationic Cycloaddition–Cyclization Cascade

We report the concise, biomimetic total synthesis of the dimeric, Diels–Alder natural product griffi­pavi­xanthone from a readily accessible prenylated xanthone monomer. The key step utilizes a novel inter­molecular [4+2] cycloaddition–cyclization cascade between a vinyl <i>p-</i>quinone methide and an <i>in situ</i> generated isomeric diene promoted by either Lewis or Brønsted acids. Experimental and computational studies of the reaction pathway suggest that a stepwise, cationic Diels–Alder cycloaddition is operative

Concerted vs Stepwise Mechanisms in Dehydro-Diels–Alder Reactions

The Diels–Alder reaction is not limited to 1,3-dienes. Many cycloadditions of enynes and a smaller number of examples with 1,3-diynes have been reported. These “dehydro”-Diels–Alder cycloadditions are one class of dehydropericyclic reactions which have long been used to generate strained cyclic allenes and other novel structures. CCSD­(T)//M05-2X computational results are reported for the cycloadditions of vinylacetylene and butadiyne with ethylene and acetylene. Both concerted and stepwise diradical routes have been explored for each reaction, with location of relevant stationary points. Relative to 1,3-dienes, replacement of one double bond by a triple bond adds 6–6.5 kcal/mol to the activation barrier; a second triple bond adds 4.3–4.5 kcal/mol to the barrier. Product strain decreases the predicted exothermicity. In every case, a concerted reaction is favored energetically. The difference between concerted and stepwise reactions is 5.2–6.6 kcal/mol for enynes but diminishes to 0.5–2 kcal/mol for diynes. Experimental studies on intramolecular diyne + ene cycloadditions show two distinct reaction pathways, providing evidence for competing concerted and stepwise mechanisms. Diyne + yne cycloadditions connect with arynes and ethynyl-1,3-cyclobutadiene. This potential energy surface appears to be flat, with only a minute advantage for a concerted process; many diyne cycloadditions or aryne cycloreversions will proceed by a stepwise mechanism

Microwave-Based Reaction Screening: Tandem Retro-Diels–Alder/Diels–Alder Cycloadditions of <i>o</i>-Quinol Dimers

We have accomplished a parallel screen of cycloaddition partners for <i>o</i>-quinols utilizing a plate-based microwave system. Microwave irradiation improves the efficiency of retro-Diels–Alder/Diels–Alder cascades of <i>o-</i>quinol dimers which generally proceed in a diastereoselective fashion. Computational studies indicate that asynchronous transition states are favored in Diels–Alder cycloadditions of <i>o</i>-quinols. Subsequent biological evaluation of a collection of cycloadducts has identified an inhibitor of activator protein-1 (AP-1), an oncogenic transcription factor