The transition state for metal-catalyzed dehalogenation

Substituent effects have been used to probe the nature of the transition state to catalytic carbon–halogen bond breaking. Kinetics measurements have determined the activation energies (E _act to C–Cl bond breaking on the Pd(111) surface and C–I bond breaking on the Pd(111) and Ag(111) surfaces. These barriers have been measured using alkyl halides with varying degrees of fluorine substitution. The activation energies have been correlated with the inductive or field substituent constants (σ_F) of the fluorinated alkyl groups in order to determine reaction constants (E _act=E₀+ρσ_F) for the dehalogenation reactions. In all three cases it has been found that the barriers are insensitive to inductive substituent effects and the reaction constants are all relatively small: ρ= −0.5± 1.0 kcal/mol for C–Cl cleavage on Pd(111), ρ= −0.3±0.8 kcal/mol for C–I cleavage on Pd(111), and ρ= −2.9±0.4 kcal/mol for C–I cleavage on Ag(111). This implies that the transition state for dehalogenation is homolytic and occurs early in the reaction coordinate. The implications of this result are discussed for catalytic dehalogenation processes such as hydrodechlorination. This revised version was published online in July 2006 with corrections to the Cover Date.     

Modeling of S‐Nitrosothiol–Thiol Reactions of Biological Significance: HNO Production by S‐Thiolation Requires a Proton Shuttle and Stabilization of Polar Intermediates

Nitroxyl (HNO), a reduced form of the important gasotransmitter nitric oxide, exhibits its own unique biological activity. A possible biological pathway of HNO formation is the S‐thiolation reaction between thiols and S‐nitrosothiols (RSNOs). Our density functional theory (DFT) calculations suggested that S‐thiolation proceeds through a proton transfer from the thiol to the RSNO nitrogen atom, which increases electrophilicity of the RSNO sulfur, followed by nucleophilic attack by thiol, yielding a charge‐separated zwitterionic intermediate structure RSS⁺(R)N(H)O^? ( Zi ), which decomposes to yield HNO and disulfide RSSR. In the gas phase, the proton transfer and the S?S bond formation are asynchronous, resulting in a high activation barrier (>40 kcal mol^?1), making the reaction infeasible. However, the barrier can decrease below the S?N bond dissociation energy in RSNOs (≈30 kcal mol^?1) upon transition into an aqueous environment that stabilizes Zi and provides a proton shuttle to synchronize the proton transfer and the S?S bond formation. These mechanistic features suggest that S‐thiolation can easily lend itself to enzymatic catalysis and thus can be a possible route of endogenous HNO production.     

Analysis of enzymatic transacylase Brønsted studies with application to the ribosome

Preferential binding of an enzyme to the transition state relative to the ground state is a key strategy for enzyme catalysis. When there is a difference between the ground and transition state charge distributions, enzymes maximize electrostatic interactions to achieve this enhanced transition state binding. Although the transition state is difficult to observe directly by structural methods, the chemical details of this transient species can be characterized by studies of substituent effects (Br?nsted, Hammett, Swain-Scott, etc.) and isotope effects. Br?nsted analysis can provide an estimate of transition state charges for the nucleophile and leaving group of a reaction. This Account will discuss the theoretical basis of Br?nsted analysis and describe its practical application to the study of transacylase enzyme systems including the peptidyl transferase reaction of the ribosome. The Br?nsted coefficient is derived from the linear free energy relationship (LFER) that correlates the acidity (pK(a)) of a reactive atom to the log of its rate constant. The Br?nsted coefficient establishes the change in atomic charge as the reaction proceeds from the ground state to the transition state. Bonding events alter the electrostatics of atoms and the extent of bonding can be extrapolated from transition state charges. Therefore, well-defined nucleophile and leaving group transition state charges limit the number of mechanisms that are consistent with a particular transition state. Br?nsted results are most informative when interpreted in the context of other mechanistic data, especially for enzymatic studies where an active site may promote a transition state that differs significantly from a prediction based on uncatalyzed solution reactions. Here we review Br?nsted analyses performed on transacylases to illustrate how these data enhanced the enzymatic mechanistic studies. Through a systematic comparison of five enzymes, we reveal a wide spectrum of Br?nsted values that are possible for what otherwise appear to be similar chemical reactions. The variations in the Br?nsted coefficients predict different transition states for the various enzymes. This Account explores an overriding theme in the enzymatic mechanisms that catalysis enhances commensurate bond formation and proton abstraction events. The extent of the two bonding events in relationship to each other can be inferred from the Br?nsted coefficient. When viewed in the context of recent ribosomal studies, this interpretation provides mechanistic insights into peptide bond formation.     

Reaction mechanism of poly(vinyl chloride) degradation. Molecular orbital calculations

Semiempirical Molecular Orbital Calculations (MNDO AM1) support kinetic results concerning the molecular mechanism of thermal degradation of PVC and show that under special conditions radical and ionic mechanisms are also possible. The degradation of poly(vinyl chloride) is a complex chain dehydrochlorination that consists of an initiation process to generate an active intermediate followed by chain reactions that generate additional active intermediates with progressively increased numbers of double bonds. Each intermediate partitions between an intermediate with one more double bond and a stable conjugated polyene with the same number of double bonds. At low and moderate temperatures thermal degradation of PVC in an inert atmosphere is a succession of molecular concerted reactions. The initiation process is a 1,2-elimination through a four center transition state requiring a synperiplanar conformation. There are two main chain reactions: the first is a 1,4-elimination from allylic chlorine atoms and methylenes cis to a double bond through a transition state of six centers; the second is a 1,3-rearrangement of hydrogen atoms catalyzed by hydrogen chloride. The chain reaction is interrupted when a relatively stable trans double bond is formed and no hydrogen chloride is present to catalyze trans-cis isomerization or 1,3-rearrangement. Macro carbocations formed by heterolysis of carbon-halogen bonds in the presence of strong Lewis acids react much faster than does the original PVC in concerted elimination by 1,2-syn or 1,4-cis mechanisms, promoting a so-called catastrophic, very fast degradation. Macro radicals formed by thermal homolysis, irradiation or reaction with promoters can also promote very fast hydrogen chloride elimination because of a special mechanism consisting of a 1,2-rearrangement of a chlorine atom followed by a concerted 1,3-elimination through a five center transition state.     

On the generation of catalytic antibodies by transition state analogues

The effective design of catalytic antibodies represents a major conceptual and practical challenge. It is implicitly assumed that a proper transition state analogue (TSA) can elicit a catalytic antibody (CA) that will catalyze the given reaction in a similar way to an enzyme that would evolve (or was evolved) to catalyze this reaction. However, in most cases it was found that the TSA used produced CAs with relatively low rate enhancement as compared to the corresponding enzymes, when these exist. The present work explores the origin of this problem, by developing two approaches that examine the similarity of the TSA and the corresponding transition state (TS). These analyses are used to assess the proficiency of the CA generated by the given TSA. Both approaches focus on electrostatic effects that have been found to play a major role in enzymatic reactions. The first method uses molecular interaction potentials to look for the similarity between the TSA and the TS and, in principle, to help in designing new haptens by using 3D quantitative structure-activity relationships. The second and more quantitative approach generates a grid of Langevin dipoles, which are polarized by the TSA, and then uses the grid to bind the TS. Comparison of the resulting binding energy with the binding energy of the TS to the grid that was polarized by the TS provides an estimate of the proficiency of the given CA. Our methods are used in examining the origin of the difference between the catalytic power of the 1F7 CA and chorismate mutase. It is demonstrated that the relatively small changes in charge and structure between the TS and TSA are sufficient to account for the difference in proficiency between the CA and the enzyme. Apparently the environment that was preorganized to stabilize the TSA charge distribution does not provide a sufficient stabilization to the TS. The general implications of our findings and the difficulties in designing a perfect TSA are discussed. Finally, the possible use of our approach in screening for an optimal TSA is pointed out.     

Isotope effects in the study of phosphoryl and sulfuryl transfer reactions

Phosphoryl and sulfuryl transfer reactions are essential biological processes. Multiple kinetic isotope effects have provided significant insights into the transition states of these reactions. The data are reviewed for the uncatalyzed reactions of phosphate and sulfate monoesters and for a number of enzymatic phosphoryl transfer reactions. Uncatalyzed phosphoryl and sulfuryl hydrolysis reactions are found to have very similar transition states. The phosphoryl transfer reaction catalyzed by protein-tyrosine phosphatases proceeds by a transition state very similar to that of the uncatalyzed reaction, but isotope effect data reveal an interesting interplay between the conserved arginine and enzyme dynamics involving general acid catalysis.     

A quantum-chemical study of adsorbed nonclassical carbonium ions as active intermediates in catalytic transformations of paraffins. II. Protolytic dehydrogenation and hydrogen-deuterium hetero-isotope exchange of paraffins on high-silica zeolites

HF-21G quantum-chemical analysis of the protolytic attack of acid protons in zeolites at the C-H bonds in methane and ethane indicated that the resulting transition states depend on the sign of the bond polarization. If a hydride ion is split off from the paraffin, then the transition state resembles the adsorbed carbonium ion and the reaction results in molecular hydrogen and in formation of the surface alkoxy group. The case, when a proton tends to split off from the paraffin, corresponds to the hetero-isotope exchange of paraffins with surface OH groups. This is a concerted acid-base reaction with a transition state different from adsorbed carbonium ion.     

Protein folding transition states: elicitation of Hammond effects by 2,2,2-trifluoroethanol

Adaptation of the techniques of classical physical-organic chemistry to the study of protein folding has led to our current detailed understanding of the transition states. Here, we have applied a series of structure--activity relationships to analyse the effects on protein folding transition states of 2,2,2-trifluoroethanol (TFE), a reagent that is usually assumed to act by stabilising secondary structure. The folding and unfolding of the highly alpha-helical tetramerisation domain of p53 provides a useful paradigm for analysing its effects on kinetics: The first step of its folding consists of an association reaction with little, if any, formation of secondary structure in the transition state; and the final step of the folding reaction involves just the formation of bonds at subunit interfaces, with the alpha-helical structure being completely formed. We have systematically measured the effects of TFE on two sets of structure--activity relationships. The first is for Phi values, which measure the degree of non-covalent bond formation at nearly every position in the transition state. The second is for relative effects of the denaturant, guanidinium chloride, on kinetics and equilibria, which measure the gross position of the transition state on the reaction co-ordinate. We find that TFE modulated the kinetics by a variety of effects other than that on secondary structure. In particular, there were Hammond effects, movement of the position of the transition state along the reaction co-ordinate, which either significantly speeded up or slowed down protein unfolding, depending on the particular mutant examined. The gross effects of TFE on protein folding kinetics are thus not a reliable guide to the structures of transition states.     

氧和氢在过渡金属上化学反应活化能估计

本文对氢、氧在过渡金属上的反应活化能以经验的键能键级（BEBO）进行预报。就表面反应的Rideal-Eley历程而言,将催化特性彼此不同的24种过渡金属分为四类:A、B、C和D。这24种金属的每一个,其表面反应的Langmuir-Hinshelwood历程活化能或反应势能皆比Rideal-Eley历程为高。在本文中,所采用的方法和实验获得的数据之间做了有利地比较;对“低化学吸附-高催化活性”这一局部催化氧化反应适用规则做了进一步地讨论。     

Design of biomimetic catalysts by molecular imprinting in synthetic polymers: the role of transition state stabilization

The impressive efficiency and selectivity of biological catalysts has engendered a long-standing effort to understand the details of enzyme action. It is widely accepted that enzymes accelerate reactions through their steric and electronic complementarity to the reactants in the rate-determining transition states. Thus, tight binding to the transition state of a reactant (rather than to the corresponding substrate) lowers the activation energy of the reaction, providing strong catalytic activity. Debates concerning the fundamentals of enzyme catalysis continue, however, and non-natural enzyme mimics offer important additional insight in this area. Molecular structures that mimic enzymes through the design of a predetermined binding site that stabilizes the transition state of a desired reaction are invaluable in this regard. Catalytic antibodies, which can be quite active when raised against stable transition state analogues of the corresponding reaction, represent particularly successful examples. Recently, synthetic chemistry has begun to match nature's ability to produce antibody-like binding sites with high affinities for the transition state. Thus, synthetic, molecularly imprinted polymers have been engineered to provide enzyme-like specificity and activity, and they now represent a powerful tool for creating highly efficient catalysts. In this Account, we review recent efforts to develop enzyme models through the concept of transition state stabilization. In particular, models for carboxypeptidase A were prepared through the molecular imprinting of synthetic polymers. On the basis of successful experiments with phosphonic esters as templates to arrange amidinium groups in the active site, the method was further improved by combining the concept of transition state stabilization with the introduction of special catalytic moieties, such as metal ions in a defined orientation in the active site. In this way, the imprinted polymers were able to provide both an electrostatic stabilization for the transition state through the amidinium group as well as a synergism of transition state recognition and metal ion catalysis. The result was an excellent catalyst for carbonate hydrolysis. These enzyme mimics represent the most active catalysts ever prepared through the molecular imprinting strategy. Their catalytic activity, catalytic efficiency, and catalytic proficiency clearly surpass those of the corresponding catalytic antibodies. The active structures in natural enzymes evolve within soluble proteins, typically by the refining of the folding of one polypeptide chain. To incorporate these characteristics into synthetic polymers, we used the concept of transition state stabilization to develop soluble, nanosized carboxypeptidase A models using a new polymerization method we term the "post-dilution polymerization method". With this methodology, we were able to prepare soluble, highly cross-linked, single-molecule nanoparticles. These particles have controlled molecular weights (39 kDa, for example) and, on average, one catalytically active site per particle. Our strategies have made it possible to obtain efficient new enzyme models and further advance the structural and functional analogy with natural enzymes. Moreover, this bioinspired design based on molecular imprinting in synthetic polymers offers further support for the concept of transition state stabilization in catalysis.     

Shape complementarity, binding-site dynamics, and transition state stabilization: a theoretical study of Diels-Alder catalysis by antibody 1E9

Antibody 1E9 is a protein catalyst for the Diels-Alder reaction between tetrachlorothiophene dioxide and N-ethylmaleimide. Quantum mechanical calculations have been employed to study the 1E9-catalyzed Diels-Alder reaction in the gas phase. The transition states and intermediates were all determined at the B3LYP/6-31G*//HF/6-31G* level. The cycloaddition step is predicted to be rate-determining, and the endo reaction pathway is strongly favored. Binding of the reactants and the transition states to antibody 1E9 was investigated by docking and molecular dynamics simulations. The linear interaction energy (LIE) method was adopted to estimate the free energy barrier of the 1E9-catalyzed Diels-Alder reaction. The catalytic efficiency of antibody 1E9 is achieved by enthalpic stabilization of the transition state, near-perfect shape complementarity of the hydrophobic binding site for the transition state, and a strategically placed hydrogen-bonding interaction.     

Cassie状态到Wenzel状态转换的能量分析

从能量的角度分析了液滴在具有圆柱形阵列的硅片表面上从Cassie状态向Wenzel状态转换的条件。通过理论计算得到了液滴在不同参数的圆柱阵列上发生状态转换所需克服的能量势垒与液滴体积之间的关系曲线,并通过实验对体积大于2 μl的液滴做了验证。实验表明,对于体积大于2 μl的液滴可以通过增大液滴重力势能的方式实现从Cassie状态到Wenzel状态的转化,也可以保持液滴体积不变,通过增大圆柱阵列的柱间距的方法实现液滴从Cassie状态到Wenzel状态的转换。实验结果与理论分析保持一致。     

Adsorption and reaction of acrolein on titanium oxide single crystal surfaces: coupling versus condensation

The reactions of acrolein have been investigated on TiO₂(0 0 1) single crystal surfaces by temperature programmed desorption (TPD), X-ray photoelectron spectroscopy (XPS) and near edge X-ray absorption fine structure (NEXAFS). Two carbon–carbon bond-forming reactions were observed. The first, on defect-containing surfaces, is reductive coupling to form olefins. The high reaction yield of ca. 80% shows the high activity of such surfaces for carbon–oxygen bond dissociation (needed for surface oxygen restoration) and carbon–carbon bond formation to make olefins. The second reaction, observed on the stoichiometric surface, is condensation of two acrolein molecules to give a C₆H₈O product tentatively identified as 2-methyl-2,4-pentadienal. Condensation reactions of carbonyls are characteristic of TiO₂ surfaces; for acrolein, this reaction is proposed to involve initial hydrogen addition followed by nucleophilic attack on a second molecule of acrolein. This results in an aldol condensation followed by dehydration.

NEXAFS analyses were conducted in order to differentiate the states of molecularly adsorbed acrolein on the two distinctly different surfaces. The C=O bond of adsorbed acrolein is maintained in the case of the stoichiometric surface (evidenced by a π_C=O^* transition at 286.6 eV), while it is absent on the reduced surface. The absence of this NEXAFS transition on the reduced surface suggests that the O atom of the C=O bond has reacted with the oxygen-deficient lattice. The restoration of these oxygen deficiencies is concomitant with the formation of the reductive coupling products (as observed by TPD and XPS experiments).     

Computer-assisted synthetic planning considering reaction kinetics based on transition state automated generation method

Organic synthesis facilitates the conversion of raw materials into high-value chemicals. Computer-assisted synthetic planning plays a vital role in designing synthetic pathways, which are usually evaluated by the reaction probability using deep learning models. However, this criterion is generally hard to describe real reaction behaviors such as reaction kinetics. Therefore, this article aims to establish a reaction kinetics-based retrosynthesis planning framework to design synthetic pathways with well-performed reaction kinetics. The key contribution of this work is developing a method for the GENeration of initial guesses of Transition States based on Reactive Sites (GENiniTS-RS) to automatically and fast generate the initial guesses of transition states for the transition state theory-based reaction kinetic model without sampling the minimum energy path from reactants to products. Finally, two case studies involving the design of synthetic pathways for aspirin and ibuprofen are presented to demonstrate the feasibility and effectiveness of the proposed framework.     

A theoretical investigation into the thiophene-cracking mechanism over pure Brønsted acidic zeolites

The mechanism of thiophene cracking catalyzed by Brønsted acidic zeolites was computed at the level of B3LYP density functional theory. It was found that this catalytic reaction involves two major steps: (1) protonation of thiophene associated with an electrophilic aromatic substitution to another thiophene in a concerted way to form 2-(2,5-dihydrothiophen-2-yl) thiophene, and (2) CS bond dissociation in 2,5-dihydrothiophene promoted by further protonation. The intermediate, 4-mercapto-1-(thiophen-2-yl)but-2-en-1-ylium, was found to have a CH₂ group close to a CC bond and a SH group, in agreement with the experimental findings. A strong stabilization effect of the zeolite framework on the transition states was found by embedding the 5T cluster into the larger 34T and 56T clusters. The rate-determining step is the electrophilic aromatic substitution.     

Dynamical resonances in the fluorine atom reaction with the hydrogen molecule

[Reaction: see text]. The concept of transition state has played a crucial role in the field of chemical kinetics and reaction dynamics. Resonances in the transition state region are important in many chemical reactions at reaction energies near the thresholds. Detecting and characterizing isolated reaction resonances, however, have been a major challenge in both experiment and theory. In this Account, we review the most recent developments in the study of reaction resonances in the benchmark F + H 2 --> HF + H reaction. Crossed molecular beam scattering experiments on the F + H 2 reaction have been carried out recently using the high-resolution, highly sensitive H-atom Rydberg tagging technique with HF rovibrational states almost fully resolved. Pronounced forward scattering for the HF (nu' = 2) product has been observed at the collision energy of 0.52 kcal/mol in the F + H 2 (j = 0) reaction. Quantum dynamical calculations based on two new potential energy surfaces, the Xu-Xie-Zhang (XXZ) surface and the Fu-Xu-Zhang (FXZ) surface, show that the observed forward scattering of HF (nu' = 2) in the F + H 2 reaction is caused by two Feshbach resonances (the ground resonance and first excited resonance). More interestingly, the pronounced forward scattering of HF (nu' = 2) at 0.52 kcal/mol is enhanced considerably by the constructive interference between the two resonances. In order to probe the resonance potential more accurately, the isotope substituted F + HD --> HF + D reaction has been studied using the D-atom Rydberg tagging technique. A remarkable and fast changing dynamical picture has been mapped out in the collision energy range of 0.3-1.2 kcal/mol for this reaction. Quantum dynamical calculations based on the XXZ surface suggest that the ground resonance on this potential is too high in comparison with the experimental results of the F + HD reaction. However, quantum scattering calculations on the FXZ surface can reproduce nearly quantitatively the resonance picture of the F + HD reaction observed in the experiment. It is clear that the dynamics of the F + HD reaction below the threshold was dominated by the ground resonance state. Furthermore, the forward scattering HF (nu' = 3) channel from the F + H 2 ( j = 0) reaction was investigated and was attributed mainly to a slow-down mechanism over the centrifugal exit barrier, with small contributions from a shape resonance mechanism in a narrow collision energy range. A striking effect of the reagent rotational excitation on resonance was also observed in F + H 2 ( j = 1), in comparison with F + H 2 ( j = 0). From these concerted experimental and theoretical studies, a clear physical picture of the reaction resonances in this benchmark reaction has emerged, providing a textbook example of dynamical resonances in elementary chemical reactions.     

Enamides and enecarbamates as nucleophiles in stereoselective C-C and C-N bond-forming reactions

Because the backbone of most of organic compounds is a carbon chain, carbon-carbon bond-forming reactions are among the most important reactions in organic synthesis. Many of the carbon-carbon bond-forming reactions so far reported rely on nucleophilic attack of enolates or their derivatives, because those nucleophiles can be, in general, readily prepared from the corresponding carbonyl compounds. In this Account, we summarize the recent development of reactions using enamide and enecarbamate as a novel type of nucleophile. Despite their ready availability and their intrinsic attraction as a synthetic tool that enables us to introduce a protected nitrogen functional group, enamide and enecarbamate have rarely been used as a nucleophile, since their nucleophilicity is low compared with the corresponding metal enolates and enamines. A characteristic of enamides and enecarbamates is that those bearing a hydrogen atom on nitrogen are relatively stable at room temperature, while enamines bearing a hydrogen atom on nitrogen are likely to tautomerize into the corresponding imine form. Enamides and enecarbamates can be purified by silica gel chromatography and kept for a long time without decomposition. During the investigation of nucleophilic addition reactions using enamides and enecarbamates, it has been revealed that enamides and enecarbamates bearing a hydrogen atom on nitrogen react actually as a nucleophile with relatively reactive electrophiles, such as glyoxylate, N-acylimino ester, N-acylimino phosphonate, and azodicarboxylate, in the presence of an appropriate Lewis acid catalyst. Those bearing no hydrogen atom on nitrogen did not react at all. The products initially obtained from the nucleophilic addition of enamides and enecarbamates are the corresponding N-protected imines, which can be readily transformed to important functional groups, such as ketones by hydrolysis and N-protected amines by reduction or nucleophilic alkylation. In the nucleophilic addition reactions of enamides and enecarbamates to aldehydes, it was unveiled that the reaction proceeds stereospecifically, that is, (E)-enecarbamate gave anti product and (Z)-enecarbamate afforded syn product with high diastereoselectivity (>97/3). This fact can be rationalized by consideration of a concerted reaction pathway via a hydrogen-involved cyclic six-membered ring transition state. In the addition reactions to N-acylimino phosphonates, much higher turnover frequency was observed when enamides and enecarbamates were used as a nucleophile than was observed when silicon enolates were used. When silicon enolates were used, the intermediates bearing a strong affinity for the catalyst inhibited catalyst turnover, resulting in low enantioslectivity because of the dominance of the uncatalyzed racemic pathway. In the case of nucleophilic addition of enamides and enecarbamate, however, a fast intramolecular hydrogen transfer from the enecarbamate nitrogen may prevent the intermediate from trapping the catalyst for a long time, to afford the product with a high enantioselectivity. In conclusion, enamides and enecarbamates, although originally employed as just N-analogues to silicon enolates, have emerged as remarkably useful nucleophiles in a variety of Lewis acid-catalyzed reactions.     

Extending NHC-catalysis: coupling aldehydes with unconventional reaction partners

Transition metal catalysis is a powerful means of effecting organic reactions, but it has some inherent drawbacks, such as the cost of the catalyst and the toxicity of the metals. Organocatalysis represents an attractive alternative and, in some cases, offers transformations unparalleled in metal catalysis. Unique transformations are a particular hallmark of N-heterocyclic carbene (NHC) organocatalysis, a versatile method for which a number of modes of action are known. The NHC-catalyzed umpolung (that is, the inversion of polarity) of electrophilic aldehydes, through formation of the nucleophilic Breslow intermediate, is probably the most important mode of action. In this Account, we discuss the reaction of Breslow intermediates with unconventional reaction partners. In two traditional umpolung reactions, the benzoin condensation and the Stetter reaction, some selectivity issues represent significant challenges, especially in intermolecular variants of these reactions. In intermolecular cross-benzoin reactions, high levels of selectivity were recently obtained, even in the hydroxymethylation of aldehydes with formaldehyde. The key to success was careful choice of the NHC catalyst and reaction conditions. Among asymmetric Stetter reactions, intermolecular versions have posed a long-standing challenge. Recently, the groups of Enders and Rovis reported the first selective and efficient systems. We have contributed to this field by developing an efficient intermolecular Stetter reaction for the formation of α-amino acid derivatives, with broad aldehyde scope and high enantiomeric excess. Moreover, tailor-made thiazolylidene catalysts allowed the unprecedented use of nonactivated olefins and alkynes as aldehyde coupling partners. The basis for this reactivity is a unique mode of NHC organocatalysis: dual activation. In a concerted but asynchronous transition state, the positively polarized proton of the Breslow intermediate activates the coupling partner (for example, an olefin), while the nucleophilic enamine moiety starts to attack the activated coupling partner. As a consequence of the concerted nature of this mechanism, excellent values for enantiomeric excess were obtained for many substrates in the intramolecular hydroacylation of alkenes. In addition, thiazolylidene catalysts have enabled the coupling of aldehydes with reactive species, for example, with arynes and with activated alkyl bromides. NHC catalysis should continue to flourish and lead to surprising developments. One remaining challenge is the asymmetric intermolecular hydroacylation of unactivated olefins. In this area, metal-based catalysts have shown promising early results, but they are far from being either general or practical. It will be interesting to see which class of catalyst, whether metal-based or NHC-based, eventually develops into the method of choice.     

Inductive Effect of Alkyl Chains on Alcohol Dehydration at Bridge-bonded Oxygen Vacancies of TiO2(110)

The activation energies for alkene formation via dehydration of alcohols on bridge-bonded oxygen (BBO) vacancy sites of TiO₂(110) is found to correlate with the inductive electron donating effect of alcohol alkyl groups as measured by the Taft parameter. Based on this correlation we conclude that the reaction involves a single transition state that undergoes concerted rupture of the C–O bond of the alkoxide and a C–H bond of the alkyl group attached to the β-carbon.