Intramolecular Heteroatom and Styryl Diels-Alder Reactions, Asymmetric Cycloadditions of Chiral 3-Phenylallyl Maleic Esters.

Polycyclic aryl naphthalene and tetralin dihydro arylnaphthalene lactone lignans possess anticancer and antibiotic activity. Related furo[3,4-c]pyranones, typified by the sequester-terpenoid isobolivianine, show similar antiproliferative bioactivity. Efficient syntheses of compounds featuring these polycyclic cores have proven challenging due to low yields and poor stereoselectivity. We report the synthesis of chiral cinnamyl but-2-enanoates and 3,3-diphenylallyl-but-2-enoates 1 as new Diels-Alder substrates. These compounds undergo [4 + 2]-cycloadditions to give furo[3,4-c]pyranones 2 in good yield (70%) and diastereoselectivity (7:1), together with naphthyl 3 and dihydronaphthyl tetralins 4 as minor products. Molecular structures and stereochemistries of the major products were verified using X-ray diffraction. Density functional theory calculations revealed that the cycloaddition process involves a bispericyclic/ambimodal process where there is a single transition state that leads to both intramolecular styryl Diels-Alder (ISDA) 3, 4 and intramolecular hetero Diels-Alder (IHDA) cycloadducts 2. With the elevated temperature conditions after cycloaddition, the resulting ISDA cycloadduct either undergoes [3,3]-sigmatropic rearrangement to the more stable major IHDA product or aromatization leading to the phenyltetralin.

Dynamical Origin of Rebound versus Dissociation Selectivity during Fe-Oxo-Mediated C-H Functionalization Reactions.

The mechanism of catalytic C-H functionalization of alkanes by Fe-oxo complexes is often suggested to involve a hydrogen atom transfer (HAT) step with the formation of a radical-pair intermediate followed by diverging pathways for radical rebound, dissociation, or desaturation. Recently, we showed that in some Fe-oxo reactions, the radical pair is a nonstatistical-type intermediate and dynamic effects control rebound versus dissociation pathway selectivity. However, the effect of the solvent cage on the stability and lifetime of the radical-pair intermediate has never been analyzed. Moreover, because of the extreme complexity of motion that occurs during dynamics trajectories, the underlying physical origin of pathway selectivity has not yet been determined. For the reaction between [(TQA_Cl)FeIVO]+ and cyclohexane, here, we report explicit solvent trajectories and machine learning analysis on transition-state sampled features (e.g., vibrational, velocity, and geometric) that identified the transferring hydrogen atom kinetic energy as the most important factor controlling rebound versus nonrebound dynamics trajectories, which provides an explanation for our previously proposed dynamic matching effect in fast rebound trajectories that bypass the radical-pair intermediate. Manual control of the reaction trajectories confirmed the importance of this feature and provides a mechanism to enhance or diminish selectivity for the rebound pathway. This led to a general catalyst design principle and proof-of-principle catalyst design that showcases how to control rebound versus dissociation reaction pathway selectivity.

Direct Dynamics Trajectories Demonstrate Dynamic Matching and Nonstatistical Radical Pair Intermediates during Fe-Oxo-Mediated C-H Functionalization Reactions.

The generally proposed mechanism for the reaction between non-heme Fe-oxo complexes and alkane C-H bonds involves a hydrogen atom transfer (HAT) reaction step with a radical pair intermediate that then has competitive radical rebound, dissociation, or desaturation pathways. Here, we report density functional theory-based quasiclassical direct dynamics trajectories that examine post-HAT reaction dynamics. Trajectories revealed that the radical pair intermediate can be a nonstatistical type intermediate without complete internal vibrational redistribution and post-HAT selectivity is generally determined by dynamic effects. Fast rebound trajectories occur through dynamic matching between the rotational motion of the newly formed Fe-OH bond and collision with the alkane radical, and all of this occurs through a nonsynchronous dynamically concerted process that circumvents the radical pair intermediate structure. For radical pair dissociation, trajectories proceeded to the radical pair intermediate for a very brief time, followed by complete dissociation. These trajectories provide a new viewpoint and model to understand the inherent reaction pathway selectivity for non-heme Fe-oxo-mediated C-H functionalization reactions.

Nature of the Trigger Linkage in Explosive Materials Is a Charge-Shift Bond.

Explosion begins by rupture of a specific bond, in the explosive, called a trigger linkage. We characterize this bond in nitro-containing explosives. Valence-bond (VB) investigations of X-NO2 linkages in alkyl nitrates, nitramines, and nitro esters establish the existence of Pauli repulsion that destabilizes the covalent structure of these bonds. The trigger linkages are mainly stabilized by covalent-ionic resonance and are therefore charge-shift bonds (CSBs). The source of Pauli repulsion in nitro explosives is unique. It is traced to the hyperconjugative interaction from the oxygen lone pairs of NO2 into the σ(X-N)* orbital, which thereby weakens the X-NO2 bond, and depletes its electron density as X becomes more electronegative. Weaker trigger bonds have higher CSB characters. In turn, weaker bonds increase the sensitivity of the explosive to impacts/shocks which lead to detonation. Application of the analysis to realistic explosives supports the CSB character of their X-NO2 bonds by independent criteria. Furthermore, other families of explosives also involve CSBs as trigger linkages (O-O, N-O, Cl-O, N-I, etc. bonds). In all of these, detonation is initiated selectively at the CSB of the molecule. A connection is made between the CSB bond-weakening and the surface-electrostatic potential diagnosis in the trigger bonds.

Electric-Field Mediated Chemistry: Uncovering and Exploiting the Potential of (Oriented) Electric Fields to Exert Chemical Catalysis and Reaction Control.

This Perspective discusses oriented external-electric-fields (OEEF), and other electric-field types, as "smart reagents", which enable in principle control over wide-ranging aspects of reactivity and structure. We discuss the potential of OEEFs to control nonredox reactions and impart rate-enhancement and selectivity. An OEEF along the "reaction axis", which is the direction whereby electronic reorganization converts reactants' to products' bonding, will accelerate reactions, control regioselectivity, induce spin-state selectivity, and elicit mechanistic crossovers. Simply flipping the direction of the OEEF will lead to inhibition. Orienting the OEEF off the reaction axis enables control over stereoselectivity, enantioselectivity, and product selectivity. For polar/polarizable reactants, the OEEF itself will act as tweezers, which orient the reactants and drive their reaction. OEEFs also affect bond-dissociation energies and dissociation modes (covalent vs ionic), as well as alteration of molecular geometries and supramolecular aggregation. The "key" to gaining access to this toolbox provided by OEEFs is microscopic control over the alignment between the molecule and the applied field. We discuss the elegant experimental methods which have been used to verify the theoretical predictions and describe various alternative EEF sources and prospects for upscaling OEEF catalysis in solvents. We also demonstrate the numerous ways in which the OEEF effects can be mimicked by use of (designed) local-electric fields (LEFs), i.e., by embedding charges or dipoles into molecules. LEFs and OEEFs are shown to be equivalent and to obey the same ground rules. Outcomes are exemplified for Diels-Alder cycloadditions, oxidative addition of bonds by transition-metal complexes, H-abstractions by oxo-metal species, ionic cleavage of halogen bonds, methane activation, etc.

Covalent vs Charge-Shift Nature of the Metal-Metal Bond in Transition Metal Complexes: A Unified Understanding.

We present here a general conceptualization of the nature of metal-metal (M-M) bonding in transition-metal (TM) complexes across the periods of TM elements, by use of ab initio valence-bond theory. The calculations reveal a dual-trend: For M-M bonds in groups 7 and 9, the 3d-series forms charge-shift bonds (CSB), while upon moving down to the 5d-series, the bonds become gradually covalent. In contrast, M-M bonds of metals having filled d-orbitals (groups 11 and 12) behave oppositely; initially the M-M bond is covalent, but upon moving down the Periodic Table, the CSB character increases. These trends originate in the radial-distribution-functions of the atomic orbitals, which determine the compactness of the valence-orbitals vis-à-vis the filled semicore orbitals. Key factors that gauge this compactness are the presence/absence of a radial-node in the valence-orbital and relativistic contraction/expansion of the valence/semicore orbitals. Whenever these orbital-types are spatially coincident, the covalent bond-pairing is weakened by Pauli-repulsion with the semicore electrons, and CSB takes over. Thus, for groups 3-10, which possess (n - 1)s2(n - 1)p6 semicores, this spatial-coincidence is maximal at the 3d-transition-metals which consequently form charge-shift M-M bonds. However, in groups 11 and 12, the relativistic effects maximize spatial-coincidence in the third series, wherein the 5d10 core approaches the valence 6s orbital, and the respective Pauli repulsion generates M-M bonds with CSB character. These considerations create a generalized paradigm for M-M bonding in the transition-elements periods, and Pauli repulsion emerges as the factor that unifies CSB over the periods of main-group and transition elements.

Oriented External Electric Fields and Ionic Additives Elicit Catalysis and Mechanistic Crossover in Oxidative Addition Reactions.

Judiciously applied oriented external electric fields (OEEFs) exert catalytic effects on the kinetics and improve the thermodynamics of chemical reactions. Herein, we examine the ability of OEEFs to assist catalysts and show that the rate of oxidative addition between palladium catalysts and alkyl/aryl electrophiles can be controlled by an OEEF applied along the direction of electron reorganization (the "reaction axis"). The concerted mechanism of oxidative addition proceeds through a transition state with moderate charge transfer character. We demonstrate that OEEFs along the reaction axis can control this charge transfer and impart electrostatic catalysis. When the applied field exceeds a certain critical value (∼0.15 V/Å), we observed a mechanistic crossover from the concerted to a dissociative CSNAr type of reactivity for aryl electrophiles. To our surprise, alkyl electrophiles follow a hitherto unexplored SN2 pathway for the reaction with large transition state stabilization at relatively low OEEFs. A valence-bond state correlation diagram (VBSCD) is employed to comprehend the results. Finally, although the catalytic effect of salt additives in oxidative addition is known, its mechanism is still under debate. Our findings further show evidence that salt additives exert electric-field effects on the rate of cross-coupling reactions, and their cocatalytic effects can be judiciously reproduced by applied external electric fields. As such, we propose that the use of additives (anionic or cationic) is an experimentally viable strategy to implement external electric-field effects in routinely used oxidative addition catalysis.

Halogen bond shortens and strengthens the bridge bond of [1.1.1]propellane and the open form of [2.2.2]propellane.

Detailed electronic structural analysis of [1.1.1]propellane and the open form of [2.2.2]propellane, especially their highest occupied molecular orbital (HOMO), shows the existence of significant electronic congestion at their bridge bond. The HOMO of [1.1.1]propellane is a spread-out orbital of its inverted tetrahedral bridgehead atoms. The HOMO of the open form of [2.2.2]propellane is an anti-bonding combination of its bridgehead atoms due to the stabilizing through-bond interaction. This unique spatial disposition of the HOMO enables a high electron density at the bridgehead atoms. Herein, we utilize the electron scavenging power of halogen bond donors to extract a fraction of destabilizing electrons from the bridge bond with the aim to alleviate its electronic congestion, which results in shortening and strengthening of the bridge bond with a reduction in the bond order. This result answers the seminal question raised by K. B. Wiberg in 1983, "how can one have a relatively 'strong bond' without much bonding character?"

A halogen bond route to shorten the ultrashort sextuple bonds in Cr2 and Mo2.

Sextuple bonded group 6 diatomics Cr2 and Mo2 possess ultrashort metal-metal bonds. Yet their bond dissociation energy is very low. The destabilising nature of σ-bonds is responsible for this. Selective extraction of these σ-electrons via a σ-hole on a halogen bond donor shortens and strengthens the metal-metal bond. This study constitutes a hitherto unexplored application of halogen bonding and an example for the true violation of bond order-bond strength relation.

Contrasting Behavior of the Z Bonds in X-Z···Y Weak Interactions: Z = Main Group Elements Versus the Transition Metals.

In contrast to the increasing family of weak intermolecular interactions in main-group compounds (X-Z···Y, Z = main-group elements), an analysis of the Cambridge Structural Database indicates that electron-saturated (18-electron) transition-metal complexes show reluctance toward weak M bond formation (X-M···Y, M = transition metal). In particular, weak M bonds involving electron-saturated (18-electron) complexes of transition metals with partially filled d-orbitals are not found. We propose that the nature of valence electron density distribution in transition-metal complexes is the primary reason for this reluctance. A survey of the interaction of selected electron-saturated transition-metal complexes with electron-rich molecules (Y) demonstrates the following: shielding the possible σ-hole on the metal center by the core electron density in 3d series, and enhanced electronegativity and relativistic effects in 4d and 5d series, hinders the formation of the M bond. A balance in all the destabilizing effects has been found in the 4d series due to its moderate polarizability and primogenic repulsion from inner core d-electrons. A changeover in the donor-acceptor nature of the metal center toward different types of incoming molecules is also unveiled here. The present study confirms the possibility of M bond as a new supramolecular force in designing the crystal structures of electron-saturated transition-metal complexes by invoking extreme ligand conditions.

Continuum in the X-Z---Y weak bonds: Z= main group elements.

The Continuum in the variation of the X-Z bond length change from blue-shifting to red-shifting through zero- shifting in the X-Z---Y complex is inevitable. This has been analyzed by ab-initio molecular orbital calculations using Z= Hydrogen, Halogens, Chalcogens, and Pnicogens as prototypical examples. Our analysis revealed that, the competition between negative hyperconjugation within the donor (X-Z) molecule and Charge Transfer (CT) from the acceptor (Y) molecule is the primary reason for the X-Z bond length change. Here, we report that, the proper tuning of X- and Y-group for a particular Z- can change the blue-shifting nature of X-Z bond to zero-shifting and further to red-shifting. This observation led to the proposal of a continuum in the variation of the X-Z bond length during the formation of X-Z---Y complex. The varying number of orbitals and electrons available around the Z-atom differentiates various classes of weak interactions and leads to interactions dramatically different from the H-Bond. Our explanations based on the model of anti-bonding orbitals can be transferred from one class of weak interactions to another. We further take the idea of continuum to the nature of chemical bonding in general.

Negative hyperconjugation and red-, blue- or zero-shift in X-Z∙∙∙Y complexes.

A generalized explanation is provided for the existence of the red- and blue-shifting nature of X-Z bonds (Z=H, halogens, chalcogens, pnicogens, etc.) in X-Z∙∙∙Y complexes based on computational studies on a selected set of weakly bonded complexes and analysis of existing literature data. The additional electrons and orbitals available on Z in comparison to H make for dramatic differences between the H-bond and the rest of the Z-bonds. The nature of the X-group and its influence on the X-Z bond length in the parent X-Z molecule largely controls the change in the X-Z bond length on X-Z∙∙∙Y bond formation; the Y-group usually influences only the magnitude of the effects controlled by X. The major factors which control the X-Z bond length change are: (a) negative hyperconjugative donation of electron density from X-group to X-Z σ* antibonding molecular orbital (ABMO) in the parent X-Z, (b) induced negative hyperconjugation from the lone pair of electrons on Z to the antibonding orbitals of the X-group, and (c) charge transfer (CT) from the Y-group to the X-Z σ* orbital. The exchange repulsion from the Y-group that shifts partial electron density at the X-Z σ* ABMO back to X leads to blue-shifting and the CT from the Y-group to the σ* ABMO of X-Z leads to red-shifting. The balance between these two opposing forces decides red-, zero- or blue-shifting. A continuum of behaviour of X-Z bond length variation is inevitable in X-Z∙∙∙Y complexes.