Paul Ha-Yeon Cheong

Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities

Organocatalysis has captured the imagination of a significant group of synthetic chemists. Much of the mechanistic understanding of these reactions has come from computational investigations or studies involving both experimental and complementary computational explorations. As much as any other area of chemistry, organocatalysis has advanced because of both empirical discoveries and computational insights. Quantum mechanical calculations, particularly with density functional theory (DFT), can now be applied to real chemical systems that are studied by experimentalists; this review describes the quantum mechanical studies of organocatalysis. The dramatic growth of computational investigations on organocatalysis in the last decade reflects the great attention focused on this area of chemistry since the discoveries of List, Lerner, and Barbas of the proline-catalyzed intermolecular aldol reaction, and by MacMillan in the area of catalysis by chiral amino-acid derived amines. The number of reports on the successful applications of organocatalysts and related mechanistic investigations for understanding the origins of catalysis and selectivities keep growing at a breathtaking pace. Literature coverage in this review is until October 2009, except for very recent discoveries that alter significantly the conclusions based on older literature. 1.1 Computational methods for organocatalysis Over the last two decades, DFT has become a method of choice for the cost-effective treatment of large chemical systems with high accuracy.1 Most of the studies reported in this review were carried out using the B3LYP functional with the 6-31G(d) basis set, which is a standard in quantum mechanical calculations. Nevertheless, DFT is experiencing continuing developments of new functionals and further improvements. The availability of many new functionals and, in particular, the rapidly evolving performance issues of B3LYP have stimulated extra efforts on benchmarking DFT methods for the prediction of key classes of organic reactions.2 The well-documented deficiencies of B3LYP include the failure to adequately describe medium-range correlation and photobranching effects,3,4 delocalization errors causing significant deviations in π→σ transformations,2b,5 and incorrect description of non-bonding and long-range interactions,6 which are likely to be key factors in determining stereoselectivities. Benchmark results also show that newer functionals considerably improve some of the underlying issues.2–7 Recent advances, especially in the treatment of dispersion effects, now offer more reliable models of the reaction profiles and stereoselectivities. Most benchmarks focus on energetics rather than stereoselectivities. Systematic benchmarking for stereoselectivities requires more sophisticated techniques and averaging over conformations. To date, such benchmarking based upon stereoselectivity is available for only three reactions,8 and even there only various basis sets with B3LYP, as well as comparisons of results predicted using enthalpies and free energies. It is not possible to assign error bars for stereoselectivities for the majority of reports discussed in this review. Because stereoisomeric transition structures are very similar species, their relative energies are likely to be calculated accurately, as shown by the good agreement between calculated and experimental values. More recently Harvey (Harvey, 2010, faraday discussions) has studied two typical organic reactions of polar species (Wittig and Morita-Baylis-Hillman reactions) at different levels of theory.2i He showed that many standard computational methods, involving B3LYP, are qualitatively useful, but the energetics may be misleading for larger reactive partners; the quantitative prediction of rate constants remains difficult. These studies suggest that although B3LYP provides valuable qualitative insight into the reaction mechanisms and selectivities, the energetics may require testing with higher accuracy methods for complex organic systems. On the other hand, Simon and Goodman found B3LYP to be “only slightly less accurate” than newer methods, and recommended its use for organic reaction mechanisms.9

Gold-Catalyzed Cycloisomerization of 1,5-Allenynes via Dual Activation of an Ene Reaction

Tris(triphenylphosphinegold) oxonium tetrafluoroborate, [(Ph3PAu)3O]BF4, catalyzes the rearrangement of 1,5-allenynes to produce cross-conjugated trienes. Experimental and computational evidence shows that the ene reaction proceeds through a unique nucleophilic addition of an allene double bond to a cationic phosphinegold(I)-complexed phosphinegold(I) acetylide, followed by a 1,5-hydrogen shift.

Computational prediction of small-molecule catalysts

Most organic and organometallic catalysts have been discovered through serendipity or trial and error, rather than by rational design. Computational methods, however, are rapidly becoming a versatile tool for understanding and predicting the roles of such catalysts in asymmetric reactions. Such methods should now be regarded as a first line of attack in the design of catalysts.

Indolyne and Aryne Distortions and Nucleophilic Regioselectivites

Density functional theory computations reproduce the surprisingly high regioselectivities in nucleophilic additions and cycloadditions to 4,5-indolynes and the low regioselectivities in the reactions of 5,6-indolynes. Transition-state distortion energies control the regioselectivities, activating the 5 and 6 positions over the 4 and 7 positions, leading to high preferences for 5- and 6-substituted products from 4,5- and 6,7-indolynes, respectively. Orbital and electrostatic interactions have only minor effects, producing low regioselectivities in the reactions of 5,6-indolynes. The distortion model predicts high regioselectivities with 6,7-indolynes; these have been verified experimentally. The regioselectivities found with other arynes are explained on the basis of distortion energies that are reflected in reactant geometries.

Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions

Efficient syntheses of 4,5-, 5,6-, and 6,7-indolyne precursors beginning from commercially available hydroxyindole derivatives are reported. The synthetic routes are versatile and allow access to indolyne precursors that remain unsubstituted on the pyrrole ring. Indolynes can be generated under mild fluoride-mediated conditions, trapped by a variety of nucleophilic reagents, and used to access a number of novel substituted indoles. Nucleophilic addition reactions to indolynes proceed with varying degrees of regioselectivity; distortion energies control regioselectivity and provide a simple model to predict the regioselectivity in the nucleophilic additions to indolynes and other unsymmetrical arynes. This model has led to the design of a substituted 4,5-indolyne that exhibits enhanced nucleophilic regioselectivity.

Origins of differences in reactivities of alkenes, alkynes, and allenes in [Rh(CO)2Cl]2-catalyzed (5 + 2) cycloaddition reactions with vinylcyclopropanes.

Rhodium dimer [Rh(CO)2Cl]2 efficiently catalyzes the intra- and intermolecular (5 + 2) reactions of vinylcyclopropanes with alkynes and allenes, but not alkenes. This difference in reactivity is attributed to the difficulty of reductive elimination for the alkene. The computed reductive elimination transition structures show that the participation of the second π-orbital in acetylene and allene reduces the barrier by 9∼15 kcal/mol, compared to ethylene, for which no such interactions are possible.

Electronic and Steric Control of Regioselectivities in Rh(I)-Catalyzed (5 + 2) Cycloadditions: Experiment and Theory

The first studies on the regioselectivity of Rh(I)-catalyzed (5 + 2) cycloadditions between vinylcyclopropanes (VCPs) and alkynes have been conducted experimentally and analyzed using density functional theory (DFT). The previously unexplored regiochemical consequences for this catalytic, intermolecular cycloaddition were determined by studying the reactions of several substituted VCPs with a range of unsymmetrical alkynes. Experimental trends were identified, and a predictive model was established. VCPs with terminal substitution on the alkene reacted with high regioselectivity (>20:1), as predicted by a theoretical model in which bulkier alkyne substituents prefer to be distal to the forming C-C bond to avoid steric repulsions. VCPs with substitution at the internal position of the alkene reacted with variable regioselectivity (ranging from >20:1 to a reversed 1:2.3), suggesting a refined model in which electron-withdrawing substituents on the alkyne decrease or reverse sterically controlled selectivity by stabilizing the transition state in which the substituent is proximal to the forming C-C bond.

Origins of regioselectivity and alkene-directing effects in nickel-catalyzed reductive couplings of alkynes and aldehydes.

The origins of reactivity and regioselectivity in nickel-catalyzed reductive coupling reactions of alkynes and aldehydes were investigated with density functional calculations. The regioselectivities of reactions of simple alkynes are controlled by steric effects, while conjugated enynes and diynes are predicted to have increased reactivity and very high regioselectivities, placing alkenyl or alkynyl groups distal to the forming C-C bond. The reactions of enynes and diynes involve 1,4-attack of the Ni-carbonyl complex on the conjugated enyne or diyne. The consequences of these conclusions on reaction design are discussed.

Substituent Effects, Reactant Preorganization, and Ligand Exchange Control the Reactivity in RhI‐Catalyzed (5+2) Cycloadditions between Vinylcyclopropanes and Alkynes

Transition-metal-catalyzed cycloadditions have become powerful reactions for the construction of carbocycles. [{Rh(CO)2Cl}2]-catalyzed (5+2) reactions between vinylcyclopropanes (VCPs) and alkynes are an effective way to construct seven-membered rings. Experimental studies have shown that siloxy, alkoxy, or alkyl group substitution at the C position of the cyclopropane is required to confer adequate reactivity of the VCPs in these reactions. The cycloaddition of 1-siloxy-, 1-alkoxy-, or 1-isopropyl-substituted VCPs with methyl propiolate provides the (5+2) cycloadducts in high yields (84–93%) in 10 min to 2 h at 40– 80 8C. Cycloaddition with the 1-methyl-substituted VCP is slower, giving 83% yield in 8 h at 80 8C. The unsubstituted VCP (R=H) is the slowest-reacting compound, giving only 23% yield in 30 h at 80 8C.We have investigated the origins of these effects using density functional theory and show that substituent effects both on transition state energetics and on reactant preorganization influence the reaction rates. Previous theoretical and mechanistic studies have shown that the (5+2) reactions occur by the catalytic cycle shown in Scheme 1. The reactions of acetylene with four VCPs (1a, R=H; 1b, R=Me; 1c, R= iPr; and 1d, R=OMe) were investigated using B3LYP/SDD-6-31G* with CPCM solvation energy corrections for CH2Cl2. The free energy surface for the reaction with 1a is shown in Figure 1. Such diagrams conventionally start with 2a, but we show the catalytic cycle beginning from the product complex 7a, which is the most stable intermediate in the catalytic cycle, and the most stable conformer of the VCP complex is s-trans-1a. The surfaces computed for other VCPs are included in the Supporting Information. The transition state for the alkyne insertion (TS3) has the highest free energy. The free energy span from complex 7 plus VCP and alkyne reactants to TS3 plus product 8 determines the rate of these cycloadditions. The VCPs 1a, 1b, and 1d adopt the s-trans conformation, while only the s-cis conformer of the Rh–VCP complex 2 can lead to the allyl intermediate 3 from which cycloadduct 8 is derived. Thus, the ground state of the VCP, the s-trans conformer, needs to be preorganized to s-cis before binding with the rhodium catalyst. Since the ground state of bulky 1c is s-cis, there is no need for a preorganization. The overall activation barrier could be broken down to three parts: the preorganization energy (DGpo) to form the scis-VCP, the free energy of exchange (DGex) to transfer the catalyst from the product complex 7 to the s-cis-VCP to form the VCP–catalyst complex 2 and liberate product 8, and the free energy of TS3 relative to reactant complex 2 (DG(TS3 2)). Thus, the observed accelerations upon substituting the C position might arise from the electronic stabilization of TS3 and the factors influencing the preorganization energy (DGpo) or ligand exchange energy (DGex). The contributions of these energies to the activation barrier are shown in Figure 2. The transition state of the alkyne insertion (TS3 ; DG(TS3 2)) is stabilized by the conjugation or hyperconjugation of the C substituent with the allyl p system. TS3d with its strongly conjugating methoxy group is 9.2 kcalmol 1 more stable relative to 2d than the unsubstituted TS3a relative to Scheme 1. Catalytic cycle for Rh-catalyzed (5+2) cycloadditions.

Mechanism and Transition-State Structures for Nickel-Catalyzed Reductive Alkyne−Aldehyde Coupling Reactions

The mechanism of nickel-catalyzed reductive alkyne-aldehyde coupling reactions has been investigated using density functional theory. The preferred mechanism involves oxidative cyclization to form the nickeladihydrofuran intermediate followed by transmetalation and reductive elimination. The rate- and selectivity-determining oxidative cyclization transition state is analyzed in detail. The d --> pi*(perpendicular) back-donation stabilizes the transition state and leads to higher reactivity for alkynes than alkenes. Strong Lewis acids accelerate the couplings with both alkynes and alkenes by coordinating with the aldehyde oxygen in the transition state.