Transition State Of Reaction Research Articles

Optimizing the surface distribution of acid sites for cooperative catalysis in condensation reactions promoted by water

Addition of small amounts of water to the organic solvent may result in different promoting or inhibiting effects in aldol condensation reactions depending on the distribution of active sites on the surface. In a combination of liquid-phase catalytic activity measurements, spectroscopies, and theoretical calculations, we have shown that water clusters around the acid site can form bridges with a ketone molecule located close to the activated carbonyl on another site. When the distance between the two acid sites is greater than a distance corresponding to about two water molecules, the efficiency of the bond polarization of the ketone by a remotely located acid site decreases significantly, and the presence of water no longer promotes the reaction. This work provides a quantitative assessment of how solvent molecules can bridge isolated active sites to enable cooperative catalysis, which offers an additional dimension for engineering catalysis at the nanoscale. • Water promotes the aldol condensation reaction by remote bond polarization • Adsorbed water on the acid site leads to H + delocalization and effective polarization • Proton delocalization is limited to about two water molecules from the original site • Water transfers the polarizing action of the acid site to the C=O bond via H bonds Nature accomplishes catalytic process with exquisite control by altering the distribution of active sites in a confining pocket and by regulating the structure of occluded solvents. In such systems, the ubiquitous water may influence reaction rates and selectivity by stabilizing reaction intermediates and transition states via a network of H bonds. Inspired by nature, here we aim at providing quantitative support and mechanistic insight into the role of water-promoting C–C bond formation on an acid catalyst by combining spectroscopic analysis, catalytic reaction measurements, and theoretical calculations. This set of experimental and computational studies reveals that the interaction between water and polar species on the surface generates diverse environments surrounding the active sites that facilitate the reaction. These findings provide an extra dimension for tailoring catalytic phenomena in industrially relevant reactions. This work emphasizes the ability of aqueous media to regulate reactivity. Upon accumulation of water around the sulfonic acid site, the proton is delocalized and transferred to two vicinal water molecules that act as a polarizing center. When the distance between two acid sites is <1 nm, water transfers the polarizing action of the acid site to the C=O bond via an H-bonded network, facilitating the C–C bond formation in condensation reactions of relevant to biomass conversion.

The Dual Effect of Coordinating −NH Groups and Light in the Electrochemical CO2 Reduction with Pyridylamino Co Complexes

AbstractCO2 electroreduction could be improved by applying conceptualized strategies to overcome catalytic bottlenecks. In this regard, we report two new cobalt(II) complexes [Co(Py2RN3)(OTf)](OTf) (CoR, R=H, Me) based on a new C2‐symmetric pentacoordinate chiral ligand that are active on the electrochemical CO2 reduction to CO. One of the complexes has a N−H group oriented towards the CO2 binding site (CoH), while the other has a N−Me group with the same orientation (CoMe), as showed by X‐ray diffraction. We have studied the effect of introducing hydrogen bonding sites, i. e. N−H in CoH, as a strategy to stabilize reaction intermediates. The complex bearing coordinating unprotected N−H group (CoH) displays catalytic CO2 reduction at the CoII/I redox potential (−1.9 V vs. Fc, ca. 40 % FYCO) whereas CoMe shows CO2 reduction at the CoI/0 redox pair. FTIR‐SEC and DFT calculations identified a [CoI−CO]+ cation as catalytic intermediate. The beneficial effect of the N−H group has been attributed to the stabilization of reaction intermediates or transition states and by the larger electron‐donating capacity, thus enhancing the nucleophilic character of the CoI intermediate. The study also points to the CO dissociation from the Co(I)−CO resting state intermediate as one of the bottlenecks of the catalytic cycle, which can be overcome with light irradiation, resulting in an increase of the total CO production (−1.9 V, 81 % FYCO, 11.2 TONCO) at the CoII/I redox potential.

Assessment of density functional theory in studying on the transition states of a Diiron-mediated N[sbnd]N bond cleavage reaction

The structure of transition state is very significant to further understand the related reaction system auxiliary NN bond cleavage process. Here, in order to sort out some DFT functionals in searching the transition states in a NN bond cleavage reaction mediated by the diiron complexes, we compared 49 density functionals with benchmark data of MP2 and DLPNO-CCSD(T) methods. By analyzing the structures and relative energies, we have found two HGGA functionals (B1B95, mPW1PBE) that are more consistently reliable ones. Among them, the B1B95 functional provides the most reliable energetic properties within 8.6 kcal/mol compared with the data of DLPNO-CCSD(T) method. And six HGGA functionals (B1B95, PBE0, mPW1PBE, mPW1PW91, HSEh1PBE, HSE1PBE) and two functionals (B2PLYP-D3, PBE0-D3) with D3 empirical dispersion well optimize the structure of Fe2S2 clusters and evaluate the reaction thermodynamic energy of NN bond cleave process. The functionals with long range correction and D3 empirical dispersion underestimate easily the energy barrier of NN bond cleavage of Fe2S2 clusters.

Partitioning Entropy with Action Mechanics: Predicting Chemical Reaction Rates and Gaseous Equilibria of Reactions of Hydrogen from Molecular Properties.

Our intention is to provide easy methods for estimating entropy and chemical potentials for gas phase reactions. Clausius’ virial theorem set a basis for relating kinetic energy in a body of independent material particles to its potential energy, pointing to their complementary role with respect to the second law of maximum entropy. Based on this partitioning of thermal energy as sensible heat and also as a latent heat or field potential energy, in action mechanics we express the entropy of ideal gases as a capacity factor for enthalpy plus the configurational work to sustain the relative translational, rotational, and vibrational action. This yields algorithms for estimating chemical reaction rates and positions of equilibrium. All properties of state including entropy, work potential as Helmholtz and Gibbs energies, and activated transition state reaction rates can be estimated, using easily accessible molecular properties, such as atomic weights, bond lengths, moments of inertia, and vibrational frequencies. We conclude that the large molecular size of many enzymes may catalyze reaction rates because of their large radial inertia as colloidal particles, maximising action states by impulsive collisions. Understanding how Clausius’ virial theorem justifies partitioning between thermal and statistical properties of entropy, yielding a more complete view of the second law’s evolutionary nature and the principle of maximum entropy. The ease of performing these operations is illustrated with three important chemical gas phase reactions: the reversible dissociation of hydrogen molecules, lysis of water to hydrogen and oxygen, and the reversible formation of ammonia from nitrogen and hydrogen. Employing the ergal also introduced by Clausius to define the reversible internal work overcoming molecular interactions plus the configurational work of change in Gibbs energy, often neglected; this may provide a practical guide for managing industrial processes and risk in climate change at the global scale. The concepts developed should also have value as novel methods for the instruction of senior students.

Cheminformatic quantum mechanical enzyme model design: A catechol-O-methyltransferase case study

To accurately simulate the inner workings of an enzyme active site with quantum mechanics (QM), not only must the reactive species be included in the model but also important surrounding residues, solvent, or coenzymes involved in crafting the microenvironment. Our lab has been developing the Residue Interaction Network Residue Selector (RINRUS) toolkit to utilize interatomic contact network information for automated, rational residue selection and QM-cluster model generation. Starting from an x-ray crystal structure of catechol-O-methyltransferase, RINRUS was used to construct a series of QM-cluster models. The reactant, product, and transition state of the methyl transfer reaction were computed for a total of 550 models, and the resulting free energies of activation and reaction were used to evaluate model convergence. RINRUS-designed models with only 200–300 atoms are shown to converge. RINRUS will serve as a cornerstone for improved and automated cheminformatics-based enzyme model design.

Chemical kinetics modeling for combustion of Al in CO2

A detailed reaction mechanism for the oxidation of aluminum with CO2 in the gas phase has been investigated. Quantum chemical calculations were performed to obtain molecular structures of reaction intermediates and transition states on the reaction pathways. A highly accurate method was applied to calculate potential energies and thermodynamic properties for the molecular structures. The rate coefficients of each reaction path were also obtained from calculations on the chemical reaction theory. A detailed chemical kinetic model was constructed from obtained rate coefficients and thermodynamic properties of molecules. Chemical kinetic analysis showed the Al + CO2 ⇔ AlO + CO reaction and Al2 + CO2 ⇔ Al2O + CO reaction were predominant in that reaction system.

Nudged Elastic Band Method for Molecular Reactions Using Energy-Weighted Springs Combined with Eigenvector Following.

The climbing image nudged elastic band method (CI-NEB) is used to identify reaction coordinates and to find saddle points representing transition states of reactions. It can make efficient use of parallel computing as the calculations of the discretization points, the so-called images, can be carried out simultaneously. In typical implementations, the images are distributed evenly along the path by connecting adjacent images with equally stiff springs. However, for systems with a high degree of flexibility, this can lead to poor resolution near the saddle point. By making the spring constants increase with energy, the resolution near the saddle point is improved. To assess the performance of this energy-weighted CI-NEB method, calculations are carried out for a benchmark set of 121 molecular reactions. The performance of the method is analyzed with respect to the input parameters. Energy-weighted springs are found to greatly improve performance and result in successful location of the saddle points in less than a thousand energy and force evaluations on average (about a hundred per image) using the same set of parameter values for all of the reactions. Even better performance is obtained by stopping the calculation before full convergence and complete the saddle point search using an eigenvector following method starting from the location of the climbing image. This combination of methods, referred to as NEB-TS, turns out to be robust and highly efficient as it reduces the average number of energy and force evaluations down to a third, to 305. An efficient and flexible implementation of these methods has been made available in the ORCA software.

Intrinsic Nucleophilicity of Inverting and Retaining Glycoside Hydrolases Revealed Using Carbasugar Glyco-Tools

Hydrolyses of cyclohexenyl-based carbasugars that mimic either α-d-glucose or α-d-galactose were explored with two Bacteroides thetaiotaomicron enzymes from glycoside hydrolase family 97: an inverting α-glucosidase (BtGH97a) and a retaining α-galactosidase (BtGH97b). Both enzymes yield nucleophilic substitutions at the pseudo-anomeric center of the carbasugar substrates, giving significantly different linear energy relationships for the catalytic rate constant as a function of the leaving group ability. Specifically, the kinetic data for the inverting α-glucosidase is consistent with the reaction giving a hydrolyzed inverted carbaglucose product by a mechanism that proceeds with little nucleophilic participation by the bound water molecule at the reaction transition state. In contrast, the reaction of carbagalactose substrates with the retaining GH97 enzyme involves a rate-limiting nonchemical step, likely a conformational change, followed by rapid substitution involving a nucleophilic amino acid residue to give a covalently bound intermediate. Considering the structural similarities between these two GH97 enzymes, the kinetic data nonetheless reveal a significant (>106) difference in the rates of nucleophilic attack between the unique enzymatic nucleophiles─with the less nucleophilic species being H2O in the inverting α-glucosidase and the better nucleophile being a carboxylate in the retaining α-galactosidase. The enzymatic rate constant ratio for the phenyl carbasugars contrasts with the corresponding kinetic data obtained using natural substrate phenyl glycopyranosides. Last, for the galactocarbasugar with a phenol leaving group, the second-order rate constant for alkylation of the GH97 α-galactosidase is only ∼10-fold lower than that for glycosylation of this enzyme by the parent carbohydrate phenyl α-d-galactopyranoside. This modest difference in rate constants underscores our conclusion that retaining glycoside hydrolases may not have optimized the nucleophilicity of their active site nucleophiles with the result that the transition state free energies for formation and hydrolysis of the covalent enzyme intermediate are matched.

Syn‐Selective Michael Reaction of α‐Branched Aryl Acetaldehydes with Nitroolefins Promoted by Squaric Amino Acid Derived Bifunctional Brønsted Bases

AbstractHere we describe a direct access to 2,2,3‐trisubstituted syn γ‐nitroaldehydes by addition of α‐branched aryl acetaldehydes to nitroolefins promoted by a cinchona based squaric acid‐derived amino acid peptide. Different α‐methyl arylacetaldehydes react with β‐aromatic and β‐alkyl nitroolefins to afford the Michael adducts in high enantioselectivity and syn‐selectivity. NMR experiments and DFT calculations predict the reaction to occur through the intermediacy of E‐enolate. The interaction between the substrates and the catalyst follows Pápai's model, wherein an intramolecular H‐bond interaction in the catalyst between the NH group of one of the tert‐leucines and the squaramide oxygen seems to be key for discrimination of the corresponding reaction transition states.

Simultaneously improving reaction coverage and computational cost in automated reaction prediction tasks.

Automated reaction prediction has the potential to elucidate complex reaction networks for applications ranging from combustion to materials degradation, but computational cost and inconsistent reaction coverage are still obstacles to exploring deep reaction networks. Here we show that cost can be reduced and reaction coverage can be increased simultaneously by relatively straightforward modifications of the reaction enumeration, geometry initialization and transition state convergence algorithms that are common to many prediction methodologies. These components are implemented in the context of yet another reaction program (YARP), our reaction prediction package with which we report reaction discovery benchmarks for organic single-step reactions, thermal degradation of a γ-ketohydroperoxide, and competing ring-closures in a large organic molecule. Compared with recent benchmarks, YARP (re)discovers both established and unreported reaction pathways and products while simultaneously reducing the cost of reaction characterization by nearly 100-fold and increasing convergence of transition states. This combination of ultra-low cost and high reaction coverage creates opportunities to explore the reactivity of larger systems and more complex reaction networks for applications such as chemical degradation, where computational cost is a bottleneck.

Staring at the Naked Goddess: Unraveling the Structure and Reactivity of Artemis Endonuclease Interacting with a DNA Double Strand.

Artemis is an endonuclease responsible for breaking hairpin DNA strands during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer therapy, both for the sensitization of radiotherapy and for immunotherapy. Despite its importance, its structure has been resolved only recently, and important questions concerning the arrangement of its active center, the interaction with the DNA substrate, and the catalytic mechanism remain unanswered. In this contribution, by performing extensive molecular dynamic simulations, both classically and at the hybrid quantum mechanics/molecular mechanics level, we evidenced the stable interaction modes of Artemis with a model DNA strand. We also analyzed the catalytic cycle providing the free energy profile and key transition states for the DNA cleavage reaction.

Molecular Details of a Coupled Binding and Folding Reaction between the Amyloid Precursor Protein and a Folded Domain.

Intrinsically disordered regions in proteins often function as binding motifs in protein–protein interactions. The mechanistic aspects and molecular details of such coupled binding and folding reactions, which involve formation of multiple noncovalent bonds, have been broadly studied theoretically, but experimental data are scarce. Here, using a combination of protein semisynthesis to incorporate phosphorylated amino acids, backbone amide-to-ester modifications, side chain substitutions, and binding kinetics, we examined the interaction between the intrinsically disordered motif of amyloid precursor protein (APP) and the phosphotyrosine binding (PTB) domain of Mint2. We show that the interaction is regulated by a self-inhibitory segment of the PTB domain previously termed ARM. The helical ARM linker decreases the association rate constant 30-fold through a fast pre-equilibrium between an open and a closed state. Extensive side chain substitutions combined with kinetic experiments demonstrate that the rate-limiting transition state for the binding reaction is governed by native and non-native hydrophobic interactions and hydrogen bonds. Hydrophobic interactions were found to be particularly important during crossing of the transition state barrier. Furthermore, linear free energy relationships show that the overall coupled binding and folding reaction involves cooperative formation of interactions with roughly 30% native contacts formed at the transition state. Our data support an emerging picture of coupled binding and folding reactions following overall chemical principles similar to those of folding of globular protein domains but with greater malleability of ground and transition states.

Stereo-dynamical effects in chemi-ionization reactions of atmospheric O2 and N2 molecules promoted by collisions with Ne*(3P2,0) atoms

This letter focuses on general aspects of the stereodynamics of chemi-ionization reactions, triggered by collisions of O2 and N2 molecules with metastable neon atoms. Basic characteristics of the long-range intermolecular forces involved, some of chemical and others of physical origin, suggest that the weakly bound precursor state, determining the reaction transition state structure and stability, is rather different. Fundamental reaction selectivities are clarified, highlighting differences in the: i) optical potential whose real and imaginary parts must be interdependent; ii) polarizability, quadrupolar moments and orbital representation of the molecules involved, which allow to lay the foundations for future more in-depth investigations.

Theoretical study on water behavior on the copper surfaces.

We calculated the adsorption of H, O, OH, and H2O and the dissociation of H2O molecule on the Cu(111), Cu(100), and Cu(110) surfaces using density functional theory. H, O, and OH tend to adsorb stably at the highly coordinated dh and h sites on the Cu(111) and Cu(100) surfaces. OH and H tend to adsorb on sb site on the Cu(110) surface. The more charge transfer of the adsorbed substance, the more stable the adsorption. The dissociation product is O+H on the Cu(111) surface, while the dissociation product is OH+H on the Cu(100) and Cu(110) surfaces. Due to the different geometric structures of initial state (IS), transition state (TS), and final state (FS) in the dissociation reaction, the dissociation of water on the copper surface does not establish a linear Brønsted-Evans-Polanyi (BEP) relationship. These results provide theoretical support for the understanding of the interaction between water and metals as well as the behavior of water molecules.

Conserved Conformational Hierarchy across Functionally Divergent Glycosyltransferases of the GT-B Structural Superfamily as Determined from Microsecond Molecular Dynamics.

It has long been understood that some proteins undergo conformational transitions en route to the Michaelis Complex to allow chemistry. Examination of crystal structures of glycosyltransferase enzymes in the GT-B structural class reveals that the presence of ligand in the active site triggers an open-to-closed conformation transition, necessary for their catalytic functions. Herein, we describe microsecond molecular dynamics simulations of two distantly related glycosyltransferases that are part of the GT-B structural superfamily, HepI and GtfA. Simulations were performed using the open and closed conformations of these unbound proteins, respectively, and we sought to identify the major dynamical modes and communication networks that interconnect the open and closed structures. We provide the first reported evidence within the scope of our simulation parameters that the interconversion between open and closed conformations is a hierarchical multistep process which can be a conserved feature of enzymes of the same structural superfamily. Each of these motions involves of a collection of smaller molecular reorientations distributed across both domains, highlighting the complexities of protein dynamic involved in the interconversion process. Additionally, dynamic cross-correlation analysis was employed to explore the potential effect of distal residues on the catalytic efficiency of HepI. Multiple distal nonionizable residues of the C-terminal domain exhibit motions anticorrelated to positively charged residues in the active site in the N-terminal domain involved in substrate binding. Mutations of these residues resulted in a reduction in negatively correlated motions and an altered enzymatic efficiency that is dominated by lower Km values with kcat effectively unchanged. The findings suggest that residues with opposing conformational motions involved in the opening and closing of the bidomain HepI protein can allosterically alter the population and conformation of the “closed” state, essential to the formation of the Michaelis complex. The stabilization effects of these mutations likely equally influence the energetics of both the ground state and the transition state of the catalytic reaction, leading to the unaltered kcat. Our study provides new insights into the role of conformational dynamics in glycosyltransferase’s function and new modality to modulate enzymatic efficiency.

Proton Bridging in Catalysis by and Inhibition of Serine Proteases of the Blood Cascade System.

Inquiries into the participation of short hydrogen bonds in stabilizing transition states and intermediate states in the thrombin, factor Xa, plasmin and activated protein C–catalyzed reactions revealed that specific binding of effectors at Sn, n = 1–4 and S’n, n = 1–3 and at remote exosites elicit complex patterns of hydrogen bonding and involve water networks. The methods employed that yielded these discoveries include; (1) kinetics, especially partial or full kinetic deuterium solvent isotope effects with short cognate substrates and also with the natural substrates, (2) kinetic and structural probes, particularly low-field high-resolution nuclear magnetic resonance (1H NMR), of mechanism-based inhibitors and substrate-mimic peptide inhibitors. Short hydrogen bonds form at the transition states of the catalytic reactions at the active site of the enzymes as they do with mechanism-based covalent inhibitors of thrombin. The emergence of short hydrogen bonds at the binding interface of effectors and thrombin at remote exosites has recently gained recognition. Herein, I describe our contribution, a confirmation of this discovery, by low-field 1H NMR. The principal conclusion of this review is that proton sharing at distances below the sum of van der Waals radii of the hydrogen and both donor and acceptor atoms contribute to the remarkable catalytic prowess of serine proteases of the blood clotting system and other enzymes that employ acid-base catalysis. Proton bridges also play a role in tight binding in proteins and at exosites, i.e., allosteric sites, of enzymes.

Rapid enthalpy prediction of transition states using molecular graph convolutional network

AbstractThe rapid development of machine learning has provided low‐cost and high‐throughput molecular energy prediction methods; however, the direct energy prediction of transition states (TSs) in radical reactions has received little attention, which can facilitate the rapid construction of potential energy surface (PES) and chemical reactivity inference. Here, we present a generic descriptor of TSs, molecules and radicals to realize the simultaneous prediction of their enthalpy of formation through the augmented molecular graph convolutional network (MGCN). It is proved that the network can rapidly (within milliseconds per prediction) and accurately predict the enthalpy of various types of samples, of which the mean absolute error (MAE) of the held‐out test set is 1.44 kcal/mol (&gt;50% samples less than 1.0 kcal/mol) with high R2 (0.925–0.998) among all categories. The PES constructed from predictions is close to the calculated results by density functional theory (DFT) and conforms to the trend of chemical reactivity.

Multiscale Simulations of SARS-CoV-2 3CL Protease Inhibition with Aldehyde Derivatives. Role of Protein and Inhibitor Conformational Changes in the Reaction Mechanism.

We here investigate the mechanism of SARS-CoV-2 3CL protease inhibition by one of the most promising families of inhibitors, those containing an aldehyde group as a warhead. These compounds are covalent inhibitors that inactivate the protease, forming a stable hemithioacetal complex. Inhibitor 11a is a potent inhibitor that has been already tested in vitro and in animals. Using a combination of classical and QM/MM simulations, we determined the binding mode of the inhibitor into the active site and the preferred rotameric state of the catalytic histidine. In the noncovalent complex, the aldehyde group is accommodated into the oxyanion hole formed by the NH main-chain groups of residues 143 to 145. In this pose, P1–P3 groups of the inhibitor mimic the interactions established by the natural peptide substrate. The reaction is initiated with the formation of the catalytic dyad ion pair after a proton transfer from Cys145 to His41. From this activated state, covalent inhibition proceeds with the nucleophilic attack of the deprotonated Sγ atom of Cys145 to the aldehyde carbon atom and a water-mediated proton transfer from the Nε atom of His41 to the aldehyde oxygen atom. Our proposed reaction transition-state structure is validated by comparison with X-ray data of recently reported inhibitors, while the activation free energy obtained from our simulations agrees with the experimentally derived value, supporting the validity of our findings. Our study stresses the interplay between the conformational dynamics of the inhibitor and the protein with the inhibition mechanism and the importance of including conformational diversity for accurate predictions about the inhibition of the main protease of SARS-CoV-2. The conclusions derived from our work can also be used to rationalize the behavior of other recently proposed inhibitor compounds, including aldehydes and ketones with high inhibitory potency.

Reaction Mechanisms and Rate Constants of Auto-Catalytic Urethane Formation and Cleavage Reactions.

The chemistry of urethanes plays a key role in important industrial processes. Although catalysts are often used, the study of the reactions without added catalysts provides the basis for a deeper understanding. For the non‐catalytic urethane formation and cleavage reactions, the dominating reaction mechanism has long been debated. To our knowledge, the reaction kinetics have not been predicted quantitatively so far. Therefore, we report a new computational study of urethane formation and cleavage reactions. To analyze various potential reaction mechanisms and to predict the reaction rate constants quantum chemistry and transition state theory were employed. For validation, experimental data from literature and from own experiments were used. Quantitative agreement of experiments and predictions could be demonstrated. The calculations confirm earlier assumptions that urethane formation reactions proceed via mechanisms where alcohol molecules act as auto‐catalysts. Our results show that it is essential to consider several transition states corresponding to different reaction orders to enable agreement with experimental observations. Urethane cleavage seems to be catalyzed by an isourethane, leading to an observed 2nd‐order dependence of the reaction rate on the urethane concentration. The results of our study support a deeper understanding of the reactions as well as a better description of reaction kinetics and will therefore help in catalyst development and process optimization.

Boronic acid with high oxidative stability and utility in biological contexts

Despite their desirable attributes, boronic acids have had a minimal impact in biological contexts. A significant problem has been their oxidative instability. At physiological pH, phenylboronic acid and its boronate esters are oxidized by reactive oxygen species at rates comparable to those of thiols. After considering the mechanism and kinetics of the oxidation reaction, we reasoned that diminishing electron density on boron could enhance oxidative stability. We found that a boralactone, in which a carboxyl group serves as an intramolecular ligand for the boron, increases stability by 104-fold. Computational analyses revealed that the resistance to oxidation arises from diminished stabilization of the p orbital of boron that develops in the rate-limiting transition state of the oxidation reaction. Like simple boronic acids and boronate esters, a boralactone binds covalently and reversibly to 1,2-diols such as those in saccharides. The kinetic stability of its complexes is, however, at least 20-fold greater. A boralactone also binds covalently to a serine side chain in a protein. These attributes confer unprecedented utility upon boralactones in the realms of chemical biology and medicinal chemistry.