Quantum Control of Gas‐Phase and Liquid‐Phase Femtochemistry

Active control of chemical reactions on a microscopic (molecular) level, that is, the selective breaking or making of chemical bonds, is an old dream. However, conventional control agents used in chemical synthesis are macroscopic variables such as temperature, pressure or concentration, which gives no direct access to the quantum‐mechanical reaction pathway. In quantum control, by contrast, molecular dynamics are guided with specifically designed light fields. Thus it is possible to efficiently and selectively reach user‐defined reaction channels. In the last years, experimental techniques were developed by which many breakthroughs in this field were achieved. Femtosecond laser pulses are manipulated in so‐called pulse shapers to generate electric field profiles which are specifically adapted to a given quantum system and control objective. The search for optimal fields is guided by an automated learning loop, which employs direct feedback from experimental output. Thereby quantum control over gas‐phase as well as liquid‐phase femtochemical processes has become possible. In this review, we first discuss the theoretical and experimental background for many of the recent experiments treated in the literature. Examples from our own research are then used to illustrate several fundamental and practical aspects in gas‐phase as well as liquid‐phase quantum control. Some additional technological applications and developments are also described, such as the automated optimization of the output from commercial femtosecond laser systems, or the control over the polarization state of light on an ultrashort timescale. The increasing number of successful implementations of adaptive learning techniques points at the great versatility of computer‐guided optimization methods. The general approach to active control of light–matter interaction has also applications in many other areas of modern physics and related disciplines.     

A Chemical Kinetic Mechanism for 2‐Bromo‐3,3,3‐trifluoropropene (2‐BTP) Flame Inhibition

In this work, we report a detailed chemical kinetic mechanism to describe the flame inhibition chemistry of the fire‐suppressant 2‐bromo‐3,3,3‐trifluoropropene (2‐BTP), under consideration as a replacement for CF₃Br. Under some conditions, the effectiveness of 2‐BTP is similar to that of CF₃Br; however, like other potential halon replacements, it failed an U.S. Federal Aviation Authority (FAA) qualifying test for its use in cargo bays. Large overpressures are observed in that test and indicate an exothermic reaction of the agent under those conditions. The kinetic model reported herein lays the groundwork to understand the seemingly conflicting behavior on a fundamental basis. The present mechanism and parameters are based on an extensive literature review supplemented with new quantum chemical calculations. The first part of the present article documents the information considered and provides traceability with respect to the reaction set, species thermochemistry, and kinetic parameters. In additional work, presented more fully elsewhere, we have combined the 2‐BTP chemical kinetic mechanism developed here with several other submodels from the literature and then used the combined mechanism to simulate premixed flames over a range of fuel/air stoichiometries and agent loadings. Overall, the modeling results qualitatively predicted observations found in cup‐burner tests and FAA Aerosol Can Tests, including the extinguishing concentrations required and the lean‐to‐rich dependence of mixtures. With these data in hand, in a second phase of the present work, we perform a reaction path analysis of major species under several modeled conditions. This analysis leads to a qualitative understanding of the ability of 2‐BTP to act as both an inhibitor and a fuel, depending on the conditions and suggests areas of the kinetic model that should be further investigated and refined.     

Capturing pressure‐dependence in automated mechanism generation: Reactions through cycloalkyl intermediates

Chemical kinetic mechanisms for gas‐phase processes (including combustion, pyrolysis, partial oxidation, or the atmospheric oxidation of organics) will often contain hundreds of species and thousands of reactions. The size and complexity of such models, and the need to ensure that important pathways are not left out, have inspired the use of computer tools to generate such large chemical mechanisms automatically. But the models produced by existing computerized mechanism generation codes, as well as a great many large mechanisms generated by hand, do not include pressure‐dependence in a general way. This is due to the difficulty of computing the large number of k(T, P) estimates required. Here we present a fast, automated method for computing k(T, P) on‐the‐fly during automated mechanism generation. It uses as its principal inputs the same high‐pressure‐limit rate estimation rules and group‐additivity thermochemistry estimates employed by existing computerized mechanism‐generation codes, and automatically identifies the important chemically activated intermediates and pathways. We demonstrate the usefulness of this approach on a series of pressure‐dependent reactions through cycloalkyl radical intermediates, including systems with over 90 isomers and 200 accessible product channels. We test the accuracy of these computer‐generated k(T, P) estimates against experimental data on the systems H + cyclobutene, H + cyclopentene, H + cyclohexene, C₂H₃ + C₂H₄, and C₃H₅ + C₂H₄, and make predictions for temperatures and pressures where no experimental data are available. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 35: 95–119, 2003     

Single‐Molecule Study of a Plasmon‐Induced Reaction for a Strongly Chemisorbed Molecule

Chemical reactions induced by plasmons achieve effective solar‐to‐chemical energy conversion. However, the mechanism of these reactions, which generate a strong electric field, hot carriers, and heat through the excitation and decay processes, is still controversial. In addition, it is not fully understood which factor governs the mechanism. To obtain mechanistic knowledge, we investigated the plasmon‐induced dissociation of a single‐molecule strongly chemisorbed on a metal surface, two O₂ species chemisorbed on Ag(110) with different orientations and electronic structures, using a scanning tunneling microscope (STM) combined with light irradiation at 5 K. A combination of quantitative analysis by the STM and density functional theory calculations revealed that the hot carriers are transferred to the antibonding (π*) orbitals of O₂ strongly hybridized with the metal states and that the dominant pathway and reaction yield are determined by the electronic structures formed by the molecule–metal chemical interaction.     

Seamless Integration of Dose‐Response Screening and Flow Chemistry: Efficient Generation of Structure–Activity Relationship Data of β‐Secretase (BACE1) Inhibitors

Drug discovery is a multifaceted endeavor encompassing as its core element the generation of structure‐activity relationship (SAR) data by repeated chemical synthesis and biological testing of tailored molecules. Herein, we report on the development of a flow‐based biochemical assay and its seamless integration into a fully automated system comprising flow chemical synthesis, purification and in‐line quantification of compound concentration. This novel synthesis‐screening platform enables to obtain SAR data on b‐secretase (BACE1) inhibitors at an unprecedented cycle time of only 1 h instead of several days. Full integration and automation of industrial processes have always led to productivity gains and cost reductions, and this work demonstrates how applying these concepts to SAR generation may lead to a more efficient drug discovery process.     

Automated chemical resonance generation and structure filtration for kinetic modeling

This work discusses efficient and automated methods for constructing a set of representative resonance structures for arbitrary chemical species, including radicals and biradicals, consisting of the elements H, C, O, N, and S. Determining the representative reactive structures of chemical species is crucial for identification of reactive sites and consequently applying the correct reaction templates to generate the set of important reactions during automated chemical kinetic model generation. We describe a fundamental set of resonance pathway types, accounting for simple resonating structures, as well as global approaches for polycyclic aromatic species. Automatically discovering potential localized structures along with filtration to identify the representative structures was shown to be robust and relatively fast. The algorithms discussed here were recently implemented in the Reaction Mechanism Generator (RMG) software. The final structures proposed by this method were found to be in reasonable agreement with quantum chemical computation results of localized structure contributions to the resonance hybrid.     

Kinetic Evidence for a Non‐Langmuir‐Hinshelwood Surface Reaction: H/D Exchange over Pd Nanoparticles and Pd(111)

The mechanism of hydrogen recombination on a Pd(111) single crystal and well‐defined Pd nanoparticles is studied using pulsed multi‐molecular beam techniques and the H₂/D₂ isotope exchange reaction. The focus of this study is to obtain a microscopic understanding of the role of subsurface hydrogen in enhancing the associative desorption of molecular hydrogen. HD production from H₂ and D₂ over Pd is investigated using pulsed molecular beams, and the temperature dependence and reaction orders are obtained for the rate of HD production under various reaction conditions designed to modulate the amount of subsurface hydrogen present. The experimental data are compared to the results of kinetic modeling based on different mechanisms for hydrogen recombination. We found that under conditions where virtually no subsurface hydrogen species are present, the HD formation rate can be described exceptionally well by a classic Langmuir–Hinshelwood model. However, this model completely fails to reproduce the experimentally observed high HD formation rates and the reaction orders under reaction conditions where subsurface hydrogen is present. To analyze this phenomenon, we develop two kinetic models that account for the role of subsurface hydrogen. First, we investigate the possibility of a change in the reaction mechanism, where recombination of one subsurface and one surface hydrogen species (known as a breakthrough mechanism) becomes dominant when subsurface hydrogen is present. Second, we investigate the possibility of the modified Langmuir–Hinshelwood mechanism with subsurface hydrogen lowering the activation energy for recombination of two hydrogen species adsorbed on the surface. We show that the experimental reaction kinetics can be well described by both kinetic models based on non‐Langmuir–Hinshelwood‐type mechanisms.     

In‐situ Chemiluminescence‐Driven Reversible Addition–Fragmentation Chain‐Transfer Photopolymerization

The power of chemical light generation (chemiluminescence) is used to drive polymerization reactions. A biphasic reaction is developed such that light‐generating reactions are confined to the organic phase and photopolymerization occurs in the aqueous phase. Well‐defined RAFT‐capped polymers are synthesized and the kinetics are shown to be dictated by light generation.     

Hydroxyl Radical Generation and DNA Nuclease Activity: A Mechanistic Study Based on a Surface‐Immobilized Copper Thioether Clip‐Phen Derivative

Coordination compounds of copper have been invoked as major actors in processes involving the reduction of molecular oxygen, mostly with the generation of radical species the assignment for which has, so far, not been fully addressed. In the present work, we have carried out studies in solution and on surfaces to gain insights into the nature of the radical oxygen species (ROS) generated by a copper(II) coordination compound containing a thioether clip‐phen derivative, 1,3‐bis(1,10‐phenanthrolin‐2‐yloxy)‐N‐(4‐(methylthio)benzylidene)propan‐2‐amine (2CP‐Bz‐SMe), enabling its adsorption/immobilization to gold surfaces. Whereas surface plasmon resonance (SPR) and electrochemistry of the adsorbed complex indicated the formation of a dimeric Cu^I intermediate containing molecular oxygen as a bridging ligand, scanning electrochemical microscopy (SECM) and nuclease assays pointed to the generation of a ROS species. Electron paramagnetic resonance (EPR) data reinforced such conclusions, indicating that radical production was dependent on the amount of oxygen and H₂O₂, thus pointing to a mechanism involving a Fenton‐like reaction that results in the production of OH^..     

Polymer‐Bound,Amphiphilic Hoveyda‐Grubbs‐Type Catalyst for Ring‐Closing Metathesis in Water

Summary: We report on the synthesis of a new amphiphilic, polymer‐bound variant of the Hoveyda‐Grubbs catalyst via the coupling reaction of a carboxylic acid‐functionalized poly(2‐oxazoline) block copolymer with 2‐isopropoxy‐5‐hydroxystyrene and subsequent reaction of the resulting macroligand with a second generation Grubbs catalyst. For the benchmark, the substrate diethyl diallylmalonate was studied in the ring‐closing metathesis (RCM) reaction and a turn‐over number (TON) of up to 390 in water was achieved. To the best of our knowledge, this is the highest value for any aqueous RCM reaction to date. For the first time, recycling of a ruthenium initiator in an aqueous RCM reaction has been successful to some extent. In addition, the micellar conditions accelerate the conversion of the hydrophobic diene and at the same time stabilize the active alkylidene species, although competing decomposition of the catalyst in water still impairs the catalyst performance. Residual ruthenium content was determined to be below 1 ppm in the product suggesting a very low leaching of the polymeric catalyst system.

Simplified chemical structure of the amphiphilic, polymer‐bound Grubbs‐Hoveyda catalyst.     

Quantum chemistry aspects of the solvent effects on the ene reaction of 1‐Phenyl‐1,3,4‐triazolin‐2,5‐dione and 2‐methyl‐2‐butene

A density functional theory study was used to investigate the quantum aspects of the solvent effects on the kinetic and mechanism of the ene reaction of 1‐phenyl‐1,3,4‐triazolin‐2,5‐dione and 2‐methyl‐2‐butene. Using the B3LYP/6–311++ G(d,p) level of the theory, reaction rates have been calculated in the various solvents and good agreement with the experimental data has been obtained. Natural bond orbital analysis has been applied to calculate the stabilization energy of N18? H19 bond during the reaction. Topological analysis of quantum theory of atom in molecule (QTAIM) studies for the electron charge density in the bond critical point (BCP) of N18? H19 bond of the transition states (TSs) in different solvents shows a linear correlation with the interaction energy. It is also seen form the QTAIM analysis that increase in the electron density in the BCP of N18? H19, raises the corresponding vibrational frequency. Average calculated ratio of 0.37 for kinetic energy density to local potential energy density at the BCPs as functions of N18? H19 bond length in different media confirmed covalent nature of this bond. Using the concepts of the global electrophilicity index, chemical hardness and electronic chemical potentials, some correlations with the rate constants and interaction energy have been established. Mechanism and kinetic studies on 1‐phenyl‐1,3,4‐triazolin‐2,5‐dione and 2‐methyl‐2‐butene ene reaction suggests that the reaction rate will boost with interaction energy enhancement. Interaction energy of the TS depends on the solvent nature and is directly related to electron density of the bonds involved in the reaction proceeding, global electrophilicity index and electronic chemical potential. However, the chemical hardness relationship is reversed. Finally, an interesting and direct correlation between the imaginary vibrational frequency of the N18? H19 critical bond and its electron density at the TS has been obtained. © 2014 Wiley Periodicals, Inc.     

The Diels–Alder Reaction of 4,6‐Dinitrobenzofuroxan with 1‐Trimethylsilyloxybuta‐1,3‐diene: A Case Example of a Stepwise Cycloaddition

The reaction of 4,6‐dinitrobenzofuroxan (DNBF) with 1‐trimethylsilyloxybuta‐1,3‐diene ( 8 ) is shown to afford a mixture of [2+4] diastereomeric cycloadducts ( 10 , 11 ) through stepwise addition–cyclization pathways. Zwitterionic intermediate σ‐adduct 9 , which is involved in the processes, has been successfully characterized by ¹H and ¹³C NMR spectroscopy and UV/visible spectrophotometry in acetonitrile. A kinetic study has been carried out in this solvent that revealed that the rate of formation of 9 nicely fits the three‐parameter equation log k=s(E+N) developed by Mayr to describe the feasibility of nucleophile–electrophile combinations. This significantly adds to the NMR spectroscopic evidence that the overall cycloadditions take place through a stepwise mechanism. The reaction has also been studied in dichloromethane and toluene. In these less polar solvents, the stability of 9 is not sufficient to allow direct characterization by spectroscopic methods, but a kinetic investigation supports the view that stepwise processes are still operating. An informative comparison of our reaction with previous interactions firmly identified as prototype stepwise cycloadditions is made on the basis of the global electrophilicity index, ω, defined by Parr within the density functional theory, and highlighted by Domingo et al. as a powerful tool for understanding Diels–Alder reactions.     

A linear solvation energy relationship study for the reactivity of 2‐(4‐substituted phenyl)‐cyclohex‐1‐enecarboxylic, 2‐(4‐substituted phenyl)‐benzoic,and 2‐(4‐substituted phenyl)‐acrylic acids with diazodiphenylmethane in various solvents

The reactivities of 2‐(4‐substituted phenyl)‐cyclohex‐1‐enecarboxylic acids, 2‐(4‐substituted phenyl)‐benzoic acids, and 2‐(4‐substituted phenyl)‐acrylic acids with diazodiphenylmethane in various solvents were investigated. To explain the kinetic results through solvent effects, the second‐order rate constants of the examined acids were correlated using the Kamlet–Taft solvatochromic equation. The correlations of the kinetic data were carried out by means of multiple linear regression analysis, and the solvent effects on the reaction rates were analyzed in terms of initial and transition state contributions. The signs of the equation coefficients support the proposed reaction mechanism. The solvation models for all investigated carboxylic acids are suggested. The quantitative relationship between the molecular structure and the chemical reactivity is discussed, as well as the effect of geometry on the reactivity of the examined molecules. © 2010 Wiley Periodicals, Inc. Int J Chem Kinet 42: 430–439, 2010     

Following the Azide‐Alkyne Cycloaddition at the Silica/Solvent Interface with Sum Frequency Generation

The Cu^I‐catalyzed 1,3‐dipolar azide‐alkyne cycloaddition (CuAAC) has arisen as one of the most useful chemical transformations for introducing complexity onto surfaces and materials owing to its functional‐group tolerance and high yield. However, methods for monitoring such reactions in situ at the widely used silica/solvent interface are hampered by challenges associated with probing such buried interfaces. Using the surface‐specific technique broadband sum frequency generation (SFG), we monitored the reaction of a benzyl azide monolayer in real time at the silica/methanol interface. A strong peak at 2096 cm^?1 assigned to the azides was observed for the first time by SFG. Using a cyano‐substituted alkyne, the decrease of the azide peak and the increase of the cyano peak (2234 cm^?1) were probed simultaneously. From the kinetic analysis, the reaction order with respect to copper was determined to be 2.1, suggesting that CuAAC on the surface follows a similar mechanism as in solution.     

Theoretical Aspects of a Surface Electrode Reaction Coupled with Preceding and Regenerative Chemical Steps: Square‐wave Voltammetry of a Surface CEC’ Mechanism

Large number of lipophilic substances, whose electrochemical transformation takes place from adsorbed state, belong to the class of so‐called “surface‐redox reactions”. Of these, especially important are the enzymatic redox reactions. With the technique named “protein‐film voltammetry” we can get insight into the chemical features of many lipophilic redox enzymes. Electrochemical processes of many redox adsorbates, occurring at a surface of working electrode, are very often coupled with chemical reactions. In this work, we focus on the application of square‐wave voltammetry (SWV) to study the theoretical features of a surface electrode reaction coupled with two chemical steps. The starting electroactive form Ox_(ads) in this mechanism gets initially generated via preceding chemical reaction. After undergoing redox transformation at the working electrode, Ox_(ads) species got additionally regenerated via chemical reaction of electrochemically generated product Red_(ads) with a given substrate Y. The theory of this so‐called surface CEC’ mechanism is presented for the first time under conditions of square‐wave voltammetry. While we present plenty of calculated voltammograms of this complex electrode mechanism, we focus on the effect of rate of regenerative (catalytic) step to simulated voltammograms. We consider both, electrochemical reactions featuring moderate and fast electron transfer. The obtained voltammetric patterns are very specific, having sometime hybrid‐like features of voltammograms as typical for CE, EC and EC’ mechanisms. We give diagnostic criteria to recognize this complex mechanism in SWV, but we also present hints to access the kinetic and thermodynamic parameters relevant to both chemical steps, and the electrochemical reaction, too. Indeed, the results presented in this work can help experimentalists to design proper experiments to study chemical features of important lipophilic systems.     

Classic and multivariate modeling treatment of the kinetics and mechanism of isomerization of 5‐cholesten‐3‐one catalyzed by sodium ethoxide

A classic kinetic methodology including the treatment of the steady‐state method and a multivariate modeling kinetic treatment were applied to the kinetics and mechanism of the isomerization reaction of 5‐cholesten‐3‐one to 4‐cholesten‐3‐one catalyzed by EtO⁻ in ethanol absolute. The rate constants, thermodynamic parameters of activation, equilibrium constant, and the isomerization enthalpy were determined. The multivariate modeling kinetic treatment allows us to calculate the concentrations of the species, in which the 3,5‐dienolate is included as a highly reactive intermediate species and was able to discriminate among several applicable mechanisms validating the one comprising two reversible steps. © 2005 Wiley Periodicals, Inc. Int J Chem Kinet 38: 38–47, 2006     

Metal‐Free Oxidative CC Bond Formation through CH Bond Functionalization

The formation of C?C bonds embodies the core of organic chemistry because of its fundamental application in generation of molecular diversity and complexity. C?C bond‐forming reactions are well‐known challenges. To achieve this goal through direct functionalization of C?H bonds in both of the coupling partners represents the state‐of‐the‐art in organic synthesis. Oxidative C?C bond formation obviates the need for prefunctionalization of both substrates. This Minireview is dedicated to the field of C?C bond‐forming reactions through direct C?H bond functionalization under completely metal‐free oxidative conditions. Selected important developments in this area have been summarized with representative examples and discussions on their reaction mechanisms.     

Spatiotemporal Kinetics in Solution Studied by Time‐Resolved X‐Ray Liquidography (Solution Scattering)

Information about temporally varying molecular structure during chemical processes is crucial for understanding the mechanism and function of a chemical reaction. Using ultrashort optical pulses to trigger a reaction in solution and using time‐resolved X‐ray diffraction (scattering) to interrogate the structural changes in the molecules, time‐resolved X‐ray liquidography (TRXL) is a direct tool for probing structural dynamics for chemical reactions in solution. TRXL can provide direct structural information that is difficult to extract from ultrafast optical spectroscopy, such as the time dependence of bond lengths and angles of all molecular species including short‐lived intermediates over a wide range of times, from picoseconds to milliseconds. TRXL elegantly complements ultrafast optical spectroscopy because the diffraction signals are sensitive to all chemical species simultaneously and the diffraction signal from each chemical species can be quantitatively calculated from its three‐dimensional atomic coordinates and compared with experimental TRXL data. Since X‐rays scatter from all the atoms in the solution sample, solutes as well as the solvent, the analysis of TRXL data can provide the temporal behavior of the solvent as well as the structural progression of all the solute molecules in all the reaction pathways, thus providing a global picture of the reactions and accurate branching ratios between multiple reaction pathways. The arrangement of the solvent around the solute molecule can also be extracted. This review summarizes recent developments in TRXL, including technical innovations in synchrotron beamlines and theoretical analysis of TRXL data, as well as several examples from simple molecules to an organometallic complex, nanoparticles, and proteins in solution. Future potential applications of TRXL in femtosecond studies and biologically relevant molecules are also briefly mentioned.