Raghavan B. Sunoj

Organoselenium chemistry: role of intramolecular interactions.

In 1836 the first organoselenium compound, diethyl selenide, was prepared by Löwig,1 and it was isolated in the pure form in 1869.2 Early selenium chemistry involved the synthesis of simple aliphatic compounds such as selenols (RSeH), selenides (RSeR), and diselenides (RSeSeR); however, because of their malodorous nature, these compounds were difficult to handle. This, combined with the instability of certain derivatives and difficulties in purification, meant that selenium chemistry was slow to develop. By the 1950s, the number of known selenium compounds had increased significantly, but it was not until the 1970s, when several new reactions leading to novel compounds with unusual properties were discovered, that selenium chemistry began to attract more general interest.3-9 Aryl-substituted compounds were synthesized that were found to be less volatile and more pleasant to handle than the earlier aliphatic compounds. Compounds containing selenium in high oxidation states are relatively easy to manipulate using modern techniques.4c Organoselenium chemistry has now become a well-established field of research, and recent advances have been brought about by the potential technical applications of selenium compounds. Today selenium compounds find application in many areas including organic synthesis,4 biochemistry,5 xerography,6 the synthesis of conducting materials7 and semiconductors,8 and ligand chemistry.4c,9 Many of these aspects of selenium chemistry are wellcovered elsewhere in the literature; however, the subject of hypervalency has not attracted much attention and is the focus of this review.10

Mechanistic Insights on N-Heterocyclic Carbene-Catalyzed Annulations: The Role of Base-Assisted Proton Transfers

The density functional theory investigation on the mechanism of NHC-catalyzed cycloannulation reaction of the homoenolate derived from butenal with pentenone is studied. The M06-2X/6-31+G** and B3LYP/6-31+G** levels of theory, including the effect of continuum solvation in dichloromethane and tetrahydrofuran, are employed. Several mechanistic scenarios are examined for each elementary step by identifying the key intermediates and the corresponding transition states interconnecting them on the respective potential energy surfaces. Both assisted and unassisted pathways for important proton transfer steps are considered, respectively, with and without the explicit inclusion of base (DBU) in the corresponding transition states. The barrier for the crucial proton transfer steps involved in the formation of the Breslow intermediate as well as in the subsequent steps is found to be significantly lowered by explicit inclusion of DBU. The energetic comparison between two key pathways, depicted as path A and path B, respectively, leading to cyclopentene and cyclopentanone derivatives, is performed. The major mechanistic bifurcation has been identified as emanating from the site of enolization of the initial zwitterionic intermediate resulting from the addition of a homoenolate equivalent to enone. If the enolization occurs nearer to the NHC moiety, the reaction is likely to proceed through path A, leading to cyclopentene. The enolization away from NHC leads to cyclopentanone product through path B. The computed results are generally in good agreement with the reported experimental results.

Non-innocent Additives in a Palladium(II)-Catalyzed C−H Bond Activation Reaction: Insights into Multimetallic Active Catalysts

The role of a widely employed additive (AgOAc) in a palladium acetate-catalyzed ortho-C-H bond activation reaction has been examined using the M06 density functional theory. A new hetero-bimetallic Pd-(μ-OAc)3-Ag is identified as the most likely active species. This finding could have far-reaching implications with respect to the notion of the active species in palladium catalysis in the presence of other metal salt additives.

Axially Chiral Imidodiphosphoric Acid Catalyst for Asymmetric Sulfoxidation Reaction: Insights on Asymmetric Induction

Insights into chiral induction for an asymmetric sulfoxidation reaction involving a single oxygen atom transfer are gained through analyzing the stereocontrolling transition states. The fitting of the substrate into the chiral cavity of a new class of imidodiphosphoric Brønsted acids, as well as weak CH⋅⋅⋅π and CH⋅⋅⋅O noncovalent interactions, are identified as responsible for the observed chiral induction.

Synthesis of 3,3-Disubstituted Oxindoles by Palladium-Catalyzed Asymmetric Intramolecular α-Arylation of Amides: Reaction Development and Mechanistic Studies

Palladium complexes incorporating chiral N-heterocyclic carbene (NHC) ligands catalyze the asymmetric intramolecular α-arylation of amides producing 3,3-disubstituted oxindoles. Comprehensive DFT studies have been performed to gain insight into the mechanism of this transformation. Oxidative addition is shown to be rate-determining and reductive elimination to be enantioselectivity-determining. The synthesis of seven new NHC ligands is detailed and their performance is compared. One of them, L8, containing a tBu and a 1-naphthyl group at the stereogenic centre, proved superior and was very efficient in the asymmetric synthesis of fifteen new spiro-oxindoles and three azaspiro-oxindoles often in high yields (up to 99 %) and enantioselectivities (up to 97 % ee; ee=enantiomeric excess). Three palladacycle intermediates resulting from the oxidative addition of [Pd(NHC)] into the aryl halide bond were isolated and structurally characterized (X-ray). Using these intermediates as catalysts showed alkene additives to play an important role in increasing turnover number and frequency.

Mechanistic insights and the Role of Cocatalysts in Aza-Morita-Baylis-Hillman and Morita-Baylis-Hillman Reactions

The mechanism of the trimethylamine or trimethylphosphine catalyzed aza-Morita-Baylis-Hillman (MBH) reaction between acrolein and mesyl imine is investigated by using ab initio and density functional methods. All key transition states are located at the CBS-4M as well as at the mPW1K/6-31+G** levels of theories. To account for the experimentally known rate enhancements through the use of polar protic cocatalysts, transition state models with explicit cocatalysts are considered. Inclusion of polar protic cocatalysts is found to have a profound influence in decreasing the activation barriers associated with the key elementary steps. The protic cocatalysts such as water, methanol, and formic acid are identified as effective in promoting a relay proton transfer. Interestingly, the efficiency of the relay mechanism results in relatively better stabilization of the proton transfer transition state as compared to the addition of enolate to the electrophile (C-C bond formation). The cocatalyst bound models suggest that the proton transfer could become the rate-determining step in the aza-MBH reaction under polar protic conditions. A comparison of the aza-MBH reaction with the analogous MBH reaction is also attempted to bring out the subtle differences between these two reactions. Enhanced kinetic advantages arising from the nature of the activated electrophile are noticed for the aza-MBH reaction. The difference in the relative energies between the transition states for the proton transfer and the C-C bond formation steps with bound cocatalyst(s) is found to be more pronounced in the aza-MBH reaction. In general, the reported results underscore the importance of considering explicit solvents/cocatalysts in order to account for the likely role of the specific interactions between reactants and solvents/cocatalysts.

Microsolvated transition state models for improved insight into chemical properties and reaction mechanisms

Over the years, several methods have been developed to effectively represent the chemical behavior of solutes in solvents. The environmental effects arising due to solvation can generally be achieved either through inclusion of discrete solvent molecules or by inscribing into a cavity in a homogeneous and continuum dielectric medium. In both these approaches of computational origin, the perturbations on the solute induced by the surrounding solvent are at the focus of the problem. While the rigor and method of inclusion of solvent effects vary, such solvation models have found widespread applications, as evident from modern chemical literature. A hybrid method, commonly referred to as cluster-continuum model (CCM), brings together the key advantages of discrete and continuum models. In this perspective, we intend to highlight the latent potential of CCM toward obtaining accurate estimates on a number of properties as well as reactions of contemporary significance. The objective has generally been achieved by choosing illustrative examples from the literature, besides expending efforts to bring out the complementary advantages of CCM as compared to continuum or discrete solvation models. The majority of examples emanate from the prevalent applications of CCM to organic reactions, although a handful of interesting organometallic reactions have also been discussed. In addition, increasingly accurate computations of properties like pK(a) and solvation of ions obtained using the CCM protocol are also presented.

Palladium(II)-catalyzed direct alkoxylation of arenes: evidence for solvent-assisted concerted metalation deprotonation.

Density functional theory investigations on the mechanism of palladium acetate catalyzed direct alkoxylation of N-methoxybenzamide in methanol reveal that the key steps involve solvent-assisted N-H as well as C-H bond activations. The transition state for the critical palladium-carbon bond formation through a concerted metalation deprotonation (CMD) process leading to a palladacycle intermediate has been found to be more stable in the methanol-assisted pathway as compared to an unassisted route.

Transition State Models for Probing Stereoinduction in Evans Chiral Auxiliary-Based Asymmetric Aldol Reactions

The use of chiral auxiliaries is one of the most fundamental protocols employed in asymmetric synthesis. In the present study, stereoselectivity-determining factors in a chiral auxiliary-based asymmetric aldol reaction promoted by TiCl(4) are investigated by using density functional theory methods. The aldol reaction between chiral titanium enolate [derived from Evans propionyl oxazolidinone (1a) and its variants oxazolidinethione (1b) and thiazolidinethione (1c)] and benzaldehyde is examined by using transition-state modeling. Different stereochemical possibilities for the addition of titanium enolates to aldehyde are compared. On the basis of the coordination of the carbonyl/thiocarbonyl group of the chiral auxiliary with titanium, both pathways involving nonchelated and chelated transition states (TSs) are considered. The computed relative energies of the stereoselectivity-determining C-C bond formation TSs in the nonchelated pathway, for both 1a and 1c, indicate a preference toward Evans syn aldol product. The presence of a ring carbonyl or thiocarbonyl group in the chiral auxiliary renders the formation of neutral TiCl(3)-enolate, which otherwise is energetically less favored as compared to the anionic TiCl(4)-enolate. Hence, under suitable conditions, the reaction between titanium enolate and aldehyde is expected to be viable through chelated TSs leading to the selective formation of non-Evans syn aldol product. Experimentally known high stereoselectivity toward Evans syn aldol product is effectively rationalized by using the larger energy differences between the corresponding diastereomeric TSs. In both chelated and nonchelated pathways, the attack by the less hindered face of the enolate on aldehyde through a chair-like TS with an equatorial disposition of the aldehydic substituent is identified as the preferred mode. The steric hindrance offered by the isopropyl group and the possible chelation are identified as the key reasons behind the interesting stereodivergence between Evans and non-Evans products normally reported for the title reaction. The application of an activation strain model on the critical TSs has been effective toward rationalizing the origin of stereoselectivity. Improved interaction energy between the reactants is found to be the key stabilizing factor for the lowest energy TS in both chelated and nonchelated pathways. The present study provides newer insights on the role of titanium(IV) toward modulating stereoselectivity in aldol reactions.

The Role of Noninnocent Solvent Molecules in Organocatalyzed Asymmetric Michael Addition Reactions

A proline-catalyzed asymmetric Michael addition between ketones and trans-beta-nitrostyrene was studied by using the density-functional theory with mPW1PW91 and B3LYP functionals. Improved insight into the enantio- and diastereoselective formation of gamma-nitroketones/-aldehydes is obtained through transition-state analysis. Consideration of the activation parameters obtained from gas-phase calculations and continuum solvation models failed to reproduce the reported experimental stereoselectivities for the reaction between cyclohexanone and 3-pentanone with trans-beta-nitrostyrene. The correct diastereo- and enantioselectivites were obtained only upon explicit inclusion of solvent molecules in the diastereomeric transition states that pertain to the C--C bond formation. Among the several transition-state models that were examined, the one that exhibits cooperative hydrogen-bonding interactions with two molecules of methanol could explain the correct stereochemical outcome of the Michael reaction. The change in differential stabilization that arises as a result of electrostatic and hydrogen-bonding interactions in the key transition states is identified as the contributing factor toward obtaining the correct diastereomer. This study establishes the importance of including explicit solvent molecules in situations in which the gas-phase and continuum models are inadequate in obtaining meaningful insight regarding experimental stereoselectivities.