A mechanistic analysis of the Birch Reduction.

The Birch Reduction is one of the main reactions of organic chemistry. The reaction involves the reaction of dissolving metals in ammonia with aromatic compounds to produce 1,4-cyclohexadienes. Discovered by Arthur Birch in 1944, the reaction occupies 300 pages in Organic Reactions to describe its synthetic versatility. Thus, it is remarkable that the reaction mechanism has been so very controversial and only relatively recently has been firmly established. Perhaps this is not that surprising, since the reaction also has many unusual and esoteric mechanistic facets. Here, I provide a description of how I have applied ever-evolving levels of quantum mechanics and a novel experimental test to understand details of the mechanism and the origins of the selectivities observed in the Birch reduction. The reaction involves an initial radical anion resulting from introduction of an electron from the blue liquid ammonia solution of free electrons formed by the dissolution of Li or related metals. This radical anion is protonated by an alcohol and then further reduced to a carbanion. Finally, the carbanion is protonated using a second proton to afford a nonconjugated cyclohexadiene. The regiochemistry depends on substituents present. With 18 resonance structures in the case of anisole radical anion, prediction of the initial protonation site would seem difficult. Nevertheless, computational methods from Hückel theory through modern density functional calculations do correctly predict the site of protonation. An esoteric test established this mechanism experimentally. The nature of the carbanion also is of mechanistic interest, and the preponderance of the resonance structure shown was revealed from Hückel calculations involving variable bond orders. For the trianion from benzoic acid, parallel questions about structure are apparent, and have been answered. Some mechanistic questions are answered experimentally and some by modern computations. Recently, our mechanistic understanding has led to a variety of synthetic applications. For example, the preparation of alkyl aromatics from benzoic acids makes use of the intermediates formed in these reactions. This Account provides an overview of both experimental techniques and theoretical methodology used to provide detailed mechanistic understanding of the Birch Reduction.

Heterocyclic photochemistry in contrast with carbon behavior. Regioselective photochemical rearrangement of an azacyclohexadienone: mechanistic and exploratory organic photochemistry.

The Type-A photochemistry of cyclohexadienones is well-studied and follows a well-established mechanistic pathway. One early example is the rearrangement of santonin to lumisantonin. Another example is the rearrangement of 4,4-diphenylcyclohexa-1,5-dienone. Remarkably, replacement of one carbon by nitrogen alters the reaction course to give a regioselective phenyl migration.

Triplet photochemistry of vinyl cyclopropenes: mechanistic and exploratory organic photochemistry.

Our research on the triplet photochemistry of vinylcyclopropenes has dealt with a diverse series of systems, providing a series of experimental examples and mechanstic studies. It perhaps is not surprising that the reaction mechanisms have been controversial. The present study is theoretical and provides evidence for control by a critical T(1) diradical intermediate which has a high spin-orbit coupling with S(0) ground-state along the mechanistic pathway. The evidence now for the one pathway derives from independent generation and behavior of this diradical, prediction of the reaction regioselectivity in nine diverse examples, the S(0) and T(1) hypersurfaces in the reaction, and an S(0)-T(1) degeneracy with SOC for the critical diradical. This triplet diradical when independently generated gives the same regioselectivity observed in examples starting with the vinylcyclopropene triplet itself. The overall reaction provides a useful synthesis of cyclopentadienes.

2-Meth-oxy-3,4-diphenyl-phenol.

The title compound, C(19)H(16)O(2), was isolated as the major product after the solid-state photochemical reaction of 2-meth-oxy-4,4-diphenyl-cyclo-hexa-2,5-dienone. The dihedral angles between the central ring and pendant benzene rings are 60.76 (6) and 51.64 (6)°. The O-C vector of the meth-oxy group is almost perpendicular to the plane of the central ring as indicated by the C-C-O-C torsion angle of 94.89 (18)°. Hydrogen-bonded dimers are formed in the crystal structure via O-H⋯O inter-actions. The data were collected at room temperature on a Bruker SMART X2S diffractometer in the automated mode and processed manually thereafter.

The aza-type-B photochemical rearrangement: the role of a second carbonyl in heterocyclic photochemistry. Mechanistic and exploratory organic photochemistry.

In contrast to the photochemistry of monocyclic aza-cyclohexenones, their counterparts with a second carbonyl group undergo photochemical rearrangements which parallel those of the 4,4-disubstituted cyclohexenones.

Conical intersection control of heterocyclic photochemical bond scission.

The photochemistry of the heterocycle 5,6-dihydro-1-methyl-5,5-diphenylpyridin-2(1H)-one (compound 1 in the text) leads to two competitive reactions (the reactions are depicted in the Introduction to the article). These arise from fission of bond a, between the nitrogen (N-6) and C-1, and bond b, between C-4, with the two phenyl substituents, and C-5, adjacent to the nitrogen. Scission of bond a alone leads to a zwitterionic intermediate which can be trapped by nucleophiles, while cleavage of bonds a and b together affords two fragments--a ketene and an imine. The ketene could be intercepted with nucleophiles and the imine trimerized. Computation reveals little weakening of bonds a and b. But as stretching begins, conical intersections are encountered, leading to ground-state products.

Control of stereoselective protonation of enols1,2.

A decalyl framework with a siloxy enolic moiety and proximate proton transferring groups was synthesized. On enolate generation with fluoride two competitive reaction modes were possible: (a) intermolecular protonation, and (b) intramolecular proton transfer by the proximate group. Control of the protonation stereochemistry proved possible by varying the proximate group and by changing the acidity of the medium. With the groups -CH2OH, -CH=O, and -CH2OCH2OCH3 as the proximate groups, only intermolecular proton transfer was observed with no dependence on acidity. In contrast, with -COO- and COOH, only intramolecular protonation resulted but again with no dependence on acidity of the medium. In contrast, with -CH2NH2 as the proximate group, intramolecular proton transfer predominated with a dependence on the effective pH of the medium. A kinetic analysis provided a linear-log relationship of the ratio of the two stereoisomers with the medium acidity. The analysis revealed that two acetic acid molecules are involved in providing the proton to the enolate moiety. A theoretical analysis was developed paralleling the experimental results. In the ketonization transition state, the hybridization was shown to be close to sp2 hybridized at the alpha-enolate carbon.

Control of proton transfer: intramolecular vs intermolecular.

[reaction: see text] Proton transfer in ketonization of enolates is a critical step in a myriad of organic reactions. Its stereochemistry has been the object of our studies since we reported kinetic protonation from the less hindered face of the molecule under kinetic control some decades ago. Very recently, we have succeeded in reversing the stereochemistry using 2-pyridyl groups to deliver the proton. We now report intramolecular delivery by other moieties and control of intramolecular versus intermolecular proton delivery.

Synthesis of a highly reactive heterocyclic reactant and its unusual photochemistry; mechanistic and exploratory organic photochemistry.

[reaction: see text] A unique new set of reactions has been observed in heterocyclic photochemistry. 2-Methyl-4,4-diphenyl-3,4-dihydropyrimidin-1(2H)-one has been synthesized and its photochemistry investigated. This compound has been found to lead to a rearranged, dimeric product arising from a unique bond-scission process.

The alpha-effect in the stereochemistry of kinetic ketonization of enols.

Kinetic control of the stereoselectivity of protonation of enolates and other strongly delocalized anionic species is involved in a large number of organic reactions. Protonation occurring from the less hindered side of the, e.g., enolic system affords the less stable of two diastereomers. However, one apparent discrepancy has been in the synthesis of prostaglandins. The present research deals with the source of this behavior. A curious effect of the substituent at the enolic alpha carbon was uncovered. In certain instances an alpha substituent is forced to twist into a conformation blocking the proton donor from its side, thus reversing the stereochemistry of protonation. In the course of this research, a number of five-ring enols of varying structure were investigated. Finally, the ketonization reaction course has been studied theoretically.

Regioselectivity of the tri-pi-methane rearrangement: mechanistic and exploratory organic photochemistry.

The di-pi-methane rearrangement with two pi-groups attached to the central "methane carbon" of the reactant and which leads to a pi-substituted cyclopropane has been studied intensively. Our present research had the goal of elucidating the regioselectivity of the tri-pi-methane counterpart. The reactants with three pi groups attached to the central carbon mechanistically are capable of affording both di-pi-methane and tri-pi-methane photoproducts. In common with the di-pi-methane system, bridging of two of the pi-systems affords a cyclopropyldicarbinyl diradical intermediate that opens to an allyl carbinyl diradical. This diradical has the option of closing to a three-membered or a five-membered ring. It was found that the regioselectivity of the initial pi-pi-bridging step and the three-ring opening of the cyclopropyldicarbinyl diradical exhibit regioselectivity parallel to that of the di-pi counterpart. Both three-ring and five-ring photoproducts were formed with the ratio varying with conversion. Since the three-ring (i.e. di-pi-methane) photoproducts were found to ring expand to the five-ring (i.e. tri-pi-methane) products, kinetics were employed to determine to what extent the reaction proceeds in a two-step versus direct formation of the five-ring product. It was found that the direct route was the major one.

An experimental and theoretical study of the type C enone rearrangement: mechanistic and exploratory organic photochemistry.

We recently described a new photochemical rearrangement which we termed a Type C process. The reaction involves a delta to alpha aryl migration in 5-disubstituted cyclohexenones also having bulky C-3 substituents. In contrast to most cyclohexenone rearrangements, the reaction occurs via a twisted pi-pi excited triplet rather than the usual n-pi state. The electronic nature of the rearrangement was assessed using migration selectivity with p-anisyl and p-cyanophenyl groups. A synthesis of the reactants was elaborated, and the product structures were established by X-ray and NMR analysis. The reaction mechanism was established further with DFT and CASSCF computations. In the latter, localized NBO basis orbitals permitted proper selection of the active space. The nature of the diradical intermediates as well as the transition states was established computationally. Sensitization experiments with regioselectivities the same as those in direct irradiation confirmed the triplet multiplicity of the process.

Solution and crystal lattice effects on the photochemistry of 6-substituted cyclohexenones(1)(,)(2).

The photochemistry of 13 4,4-diphenylcyclohexenones, substituted at carbon-6, was investigated in solution and in the crystalline state. The stereoselectivity was of particular interest. In the solution photochemistry of C-6 monosubstituted enones in benzene, there was a unique preference for migration of the cis-phenyl group with formation of bicyclo[3.1.0]hexanone photoproducts, with the original 6-substituent having an endo configuration at carbon-3 of the product. In methanol the reaction was diverted to afford 3,4-diphenylcyclohex-2-enes understood as arising from a hydrogen-bonded zwitterionic intermediate. The solid-state photochemistry was also investigated. There was a dramatic absence of the 3,4-diphenylcyclohex-2-ene products in accord with the absence of the hydrogen bonding encountered in methanol. Further, the solid-state reactivity correlated with a vector analysis using X-ray atomic coordinates. This established that the migrating phenyl group required an orientation facing the enone beta-carbon. While the interesting preference for the cis-endo migration was not intuitively predicted, ab initio computations on the alternative phenyl-bridged triplet intermediates did lead to an understanding of the selectivity.

Inter- and intramolecular stereoselective protonation of enols(1,2).

Kinetic control of the stereoselectivity of protonation of enolates and other delocalized species commonly affords the less stable diastereomer as a consequence of the considerable exothermicity and resulting sp(2) transition-state hybridization of the alpha-carbon. Protonation then is from the less hindered face of the enolate. The present study is aimed at reversing this phenomenon by intramolecular delivery of the proton. The approach employed required the synthesis of two enolate precursors, one with a 2-pyridyl group strategically close to the alpha-carbon and the other with a phenyl group in the same location. The synthesis required 15 steps and involved new methodology. Intramolecular proton transfer, reversing the usual stereoselectivity, was successful. The selectivity proved to depend on several factors including the exo versus endo configuration of the diastereomer reacting, the proton donor employed, and the concentration of the proton donor. A kinetic analysis permitted the determination of the relative reaction orders of the protonation on the two faces of the enolate.

Intramolecular proton transfer.

[structure: see text] Reversal of the normal kinetic protonation stereochemistry results as a consequence of intramolecular delivery.

The diverted di-pi-methane rearrangement; mechanistic and exploratory organic photochemistry.

[reaction: see text] An unusual diversion of the di-pi-methane rearrangement has been encountered. The reaction is characteristic of di-pi-methane systems having one vinyl group bearing one or two carbonyl groups and provides a synthesis of dihydrofurans.

Quantitative cavities and reactivity in stages of crystal lattices: mechanistic and exploratory organic photochemistry.

In continuing our research on solid-state organic photochemistry, we have been investigating the phenomenon of reactivity in stages. In this study we present new examples where the photochemical reactivity changes discontinuously at some point in the conversion. In these instances, the reaction course of the solid differs from that in solution. One example is the reaction of 2-methyl-4,4-diphenylcyclohexenone, where an unusual reaction course was encountered in the solid state; and, of two possible mechanisms, one was established by isotopic labeling. A second case is that of 4,5,5-triphenylcyclohexenone. The solid-state reaction of this enone was found to give a new photochemical transformation, the Type C rearrangement, a process that involves a delta to alpha aryl migration. In the case of 3-tert-butyl-5,5-diphenylcyclohexenone the Type C rearrangement occurred even in solution. The stage behavior was investigated using X-ray analysis and Quantum Mechanics/Molecular Mechanics computations. This permitted us to determine the sources and details of the stage phenomenon. The analysis revealed how a product molecule as a neighbor affects reactivity. The computations were employed to follow the course of a solid-state reaction from reactant through the succeeding stages. Additionally, the Delta-Density Analysis was utilized to ascertain the electronic nature of molecular changes. Besides product composition changing with extent of conversion, the reaction quantum yield was found to change as one stage gave way to a succeeding one.

Development of experimental and theoretical crystal lattice organic photochemistry: the quantitative cavity. Mechanistic and exploratory organic photochemistry.

The photochemistry of organic reactants in the crystalline state has a long history. What has been lacking is comprehensive theory defining what controls the course of these reactions which quite often afford products not obtainable in solution. Also lacking has been solid-state rearrangement chemistry with accompanying theory. In our research over the past two decades we have developed theoretical treatments of solid-state reactivity. This report describes the development of this research from its primitive beginnings to the present.

Control of the Stereochemistry of Kinetic Protonation: Intramolecular Proton Delivery(1)(,)(2).

Four decades ago, we noted that for delocalized carbanions and enols the protonation transition state is close to sp(2) hybridized and that, as a consequence, under kinetic control protonation takes place from the less hindered approach, most often with formation of the less stable of two possible stereoisomers. The initial report was followed by an extensive series of examples. Nevertheless, a major question remained, namely whether it was possible to deliver the proton to the more hindered face of such a species using intramolecular proton transfer. To this end, silyl ether precursors to the enols of 3-benzoyl-endo-6-phenyl-exo-6-pyridylbicyclo[3.1.0]hexane and its endo-6-pyridyl-exo-6-phenyl stereoisomer were synthesized. The corresponding enols were generated with fluoride anion. The endo-phenyl enol stereoisomers, on kinetic protonation, led stereoselectively to the endo-3-benzoyl product resulting from the less hindered protonation. In stark contrast, the endo-6-pyridyl enol isomer led stereoselectively to the exo-3-benzoyl ketone by intramolecular proton delivery. However, the kinetic orders of the stereochemistries differ; the intramolecular process requires additional proton donor molecules. The log of the ratio of the two stereochemistries is linear with the log of the proton donor concentration with the slope giving the difference in kinetic orders. An aromatic cyclic 14 electron Hückel transition state is proposed. Additionally, the roles of acyl, nitro and cyano delocalizing groups were analyzed with ab initio computations.