Yun-Dong Wu

Palladium-catalyzed meta-selective C-H bond activation with a nitrile-containing template: computational study on mechanism and origins of selectivity.

Density functional theory investigations have elucidated the mechanism and origins of meta-regioselectivity of Pd(II)-catalyzed C-H olefinations of toluene derivatives that employ a nitrile-containing template. The reaction proceeds through four major steps: C-H activation, alkene insertion, β-hydride elimination, and reductive elimination. The C-H activation step, which proceeds via a concerted metalation-deprotonation (CMD) pathway, is found to be the rate- and regioselectivity-determining step. For the crucial C-H activation, four possible active catalytic species-monomeric Pd(OAc)2, dimeric Pd2(OAc)4, heterodimeric PdAg(OAc)3, and trimeric Pd3(OAc)6-have been investigated. The computations indicated that the C-H activation with the nitrile-containing template occurs via a Pd-Ag heterodimeric transition state. The nitrile directing group coordinates with Ag while the Pd is placed adjacent to the meta-C-H bond in the transition state, leading to the observed high meta-selectivity. The Pd2(OAc)4 dimeric mechanism also leads to the meta-C-H activation product but with higher activation energies than the Pd-Ag heterodimeric mechanism. The Pd monomeric and trimeric mechanisms require much higher activation free energies and are predicted to give ortho products. Structural and distortion energy analysis of the transition states revealed significant effects of distortions of the template on mechanism and regioselectivity, which provided hints for further developments of new templates.

Role of N-acyl amino acid ligands in Pd(II)-catalyzed remote C-H activation of tethered arenes.

A combined experimental/computational study on the amino acid ligand-assisted Pd-catalyzed C-H bond activation reveals a mechanism in which the amino acid acts as both a dianionic bidentate ligand and a proton acceptor. This new model explains the effects of amino acids on reactivity and selectivity and unveils the dual roles of amino acids: stabilizing monomeric Pd complexes and serving as the internal base for proton abstraction.

Revealing a Second Transmetalation Step in the Negishi Coupling and Its Competition with Reductive Elimination: Improvement in the Interpretation of the Mechanism of Biaryl Syntheses

This paper presents an experimental and theoretical investigation of the Pd-catalyzed Negishi coupling reaction and reveals a novel second transmetalation reaction between an Ar(1)-Pd-Ar(2) species and the organozinc reagent Ar(2)-ZnX. Understanding of this second step reveals how homocoupling and dehalogenation products are formed. Thus, the second transmetalation generates Ar(2)PdAr(2) and Ar(1)ZnCl, which upon reductive elimination and hydrolysis, respectively, give the homocoupling product Ar(2)-Ar(2) and the dehalogenation product Ar(1)H. The ratio of the cross-coupling product Ar(1)-Ar(2) and the homocoupling product Ar(2)-Ar(2) is determined by competition between the second transmetalation and reductive elimination steps. This mechanism is further supported by density functional theoretical calculations. Calculations on a series of reactions suggest a strategy in controlling the selectivity of cross-coupling and homocoupling pathways, which we have experimentally verified.

Mechanistic Understanding of the Unexpected Meta Selectivity in Copper-Catalyzed Anilide C–H Bond Arylation

DFT calculations suggest that the unexpected meta product in the copper-catalyzed arylation of anilide is formed via a Heck-like four-membered-ring transition state involving a Cu(III)-Ph species. A competitive electrophilic substitution mechanism delivers the ortho product when a methoxy group is present at the meta position of pivanilide. A series of experiments including kinetic studies support the involvement of a Cu(I) catalyst.

Highly Diastereoselective Switchable Enantioselective Mannich Reaction of Glycine Derivatives with Imines

Tuning of diastereoselectivity was realized in the Mannich reaction of glycine derivatives with aromatic and aliphatic N-Ts imines using CuClO4-FcPHOX ligand 4b and 4f having an MeO group at the 4-position and F atom at the 3,5-position of the phenyl ring on the P-atom respectively as catalyst, providing either anti- or syn-alpha,beta-diamino acid derivatives in high yields and in high diastereo- and enantioselectivities.

Theoretical studies of stereoselective hydroborations

Abstract Asymmetric hydroborations of alkenes are outstanding examples of reactions which proceed with high acyclic stereoselection to give synthetically useful functionality. We have undertaken com- putational studies of these reactions as a part of our more general studies of stereoselective organic reactions. We wish to develop understanding of those factors which control stereoselectivity in known cases, and to develop both qualitative and quantitative methods to predict stereoselectivities of cases not yet investigated. Here, we detail our progress in understanding hydroborations, and in subsequent publications, we will report similar studies for other types of organic reactions, such as intermolecular and intramolecular cycloadditions, epoxidations, radical reactions, nucleophilic additions, and aldol condensations.

Computational Organic Chemistry: Bridging Theory and Experiment in Establishing the Mechanisms of Chemical Reactions

Understanding the mechanisms of chemical reactions, especially catalysis, has been an important and active area of computational organic chemistry, and close collaborations between experimentalists and theorists represent a growing trend. This Perspective provides examples of such productive collaborations. The understanding of various reaction mechanisms and the insight gained from these studies are emphasized. The applications of various experimental techniques in elucidation of reaction details as well as the development of various computational techniques to meet the demand of emerging synthetic methods, e.g., C-H activation, organocatalysis, and single electron transfer, are presented along with some conventional developments of mechanistic aspects. Examples of applications are selected to demonstrate the advantages and limitations of these techniques. Some challenges in the mechanistic studies and predictions of reactions are also analyzed.

Theoretical Analysis of Secondary Structures of β-Peptides

Unlike alpha-amino acids, peptides formed from beta-amino acids (beta-peptides) display stability toward enzymatic degradation and may form turns and helices with as few as four residues. Because both the C alpha and C beta of the beta-amino acid may bear substituents, a large number of beta-amino acids can be synthesized. Beta-peptides form various well-defined secondary structures, including 14-helix, 12-helix, 10/12-helix, 10-helix, 8-helix, turn structures, sheets, and hairpins. For all of these reasons, beta-amino acids have been increasingly used as building blocks for molecular design and pharmaceutical applications. To explain the conformational features of beta-peptides, several quantum mechanics and molecular dynamics studies that rationalize the observed conformational features have been reported. However, a systematic account that unifies various factors critical to the conformational features is still lacking. In this Account, we present a detailed analysis of the conformational features of various beta-peptides. We start by studying the basic local conformational features of beta-peptides using di- and tripeptide models. Then, various secondary structures of unsubstituted beta-peptides with differing numbers of residues are investigated using a repeating unit approach to derive the intrinsic backbone conformational features. We find that the 10/12-helix is intrinsically most stable for the beta-peptide backbone. The 14-helix, 12-helix, and 10-helix structures have similar stabilities for beta-peptide backbones of four to six residues. The substituent effects on the stabilities of beta-peptide secondary structures are then analyzed. Combined with the substituent effect and the intrinsic backbone preferences, all experimental observations of secondary structure formation can be understood. For example, the 10/12-helix is favored for like-beta(2)/beta(3)-peptides, unlike-beta(3)/beta(3)-peptides, and beta(3)/beta-hGly-peptides because these substitution patterns do not cause steric problems for the 10/12-helix. Beta(3)-peptides, beta(2)-peptides, and beta (2,3)-peptides favor the 14-helix because the substituents in these peptides benefit the 14-helix the most but significantly destabilize the 10/12-helix. Because the 10/12-helix is intrinsically favored and has two favorable positions in each residue for substituents, many more hybrid beta-peptides are predicted to exist in this secondary structure, which suggests the need for further experiments. These results are valuable for determining the best use of these building blocks in the design of well-structured molecules with desirable chemical functions.

Mechanism, Reactivity, and Selectivity in Palladium-Catalyzed Redox-Relay Heck Arylations of Alkenyl Alcohols

The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of β-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict a ΔΔG⧧ of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C–O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.

A Dramatic Switch of Enantioselectivity in Asymmetric Heck Reaction by Benzylic Substituents of Ligands

A series of benzylic substituted P, N-ligands 1 and 2 have been synthesized. The Pd-complexes of these ligands show high catalytic activity and enantioselectivity in catalyzing the asymmetric Heck reaction. A dramatic switch in enantioselectivity is realized using ligands with and without substituents at the benzylic position of the ligand. Ligands 1 with H as the substituents offer products in (R)-configuration while ligands 2 with the methyl as substituents result in (S)-configuration products. In most cases high enantioselectivities are achieved. Density functional theory calculations on the reaction mechanism as well as X-ray analysis of 1a-PdCl 2 and 2a-PdCl 2 complexes provide a rational explanation for the above observations.