Graham E. Garrett

Dissecting the mechanisms of a class of chemical glycosylation using primary 13C kinetic isotope effects

Although arguably the most important reaction in glycoscience, chemical glycosylations are among the least well understood of organic chemical reactions, resulting in an unnecessarily high degree of empiricism and a brake on rational development in this critical area. To address this problem, primary 13C kinetic isotope effects have now been determined for the formation of β- and α-manno- and glucopyranosides using a natural abundance NMR method. In contrast to the common current assumption, for three of the four cases studied the experimental and computed values are indicative of associative displacement of the intermediate covalent glycosyl trifluoromethanesulfonates. For the formation of the α-mannopyranosides, the experimentally determined KIE differs significantly from that computed for an associative displacement, which is strongly suggestive of a dissociative mechanism that approaches the intermediacy of a glycosyl oxocarbenium ion. The application of analogous experiments to other glycosylation systems should shed further light on their mechanisms and thus assist in the design of better reactions conditions with improved stereoselectivity. Chemical glycosylations are perhaps the most important reactions in glycoscience, but the mechanisms are not well understood. Here, quantum chemical calculations combined with natural-abundance NMR measurements of 13C kinetic isotope effects reveal both associative and dissociative mechanisms at the extremes of a continuum that depends on the relative stereochemistry of the substrate and the anomeric configuration of the product.

Chalcogen Bonding in Solution: Interactions of Benzotelluradiazoles with Anionic and Uncharged Lewis Bases

Chalcogen bonding is the noncovalent interaction between an electron-deficient, covalently bonded chalcogen (Te, Se, S) and a Lewis base. Although substantial evidence supports the existence of chalcogen bonding in the solid state, quantitative data regarding the strengths of the interactions in the solution phase are lacking. Herein, determinations of the association constants of benzotelluradiazoles with a variety of Lewis bases (Cl(-), Br(-), I(-), NO3(-) and quinuclidine, in organic solvent) are described. The participation of the benzotelluradiazoles in chalcogen bonding interactions was probed by UV-vis, (1)H and (19)F NMR spectroscopy as well as nano-ESI mass spectrometry. Trends in the free energy of chalcogen bonds upon variation of the donor, acceptor and solvent are evident from these data, including a linear free energy relationship between chalcogen bond donor ability and calculated electrostatic potential at the tellurium center. Calculations using the dispersion-corrected B97-D3 functional were found to give good agreement with the experimental free energies of chalcogen bonding.

The redox chemistry of sulfenic acids.

A persistent triptycenyl sulfenic acid is used as a model for cysteine-derived and other biologically relevant sulfenic acids in experiments which define their redox chemistry. EPR spectroscopy reveals that sulfinyl radicals are persistent and unreactive toward O(2), allowing the O-H bonding dissociation enthalpy (BDE) of the sulfenic acid to be readily determined by equilibration with TEMPO as 71.9 kcal/mol. The E° (RSO•/RSO(-)) and pK(a) of this sulfenic acid are also reported.

Leaving Group Assistance in the La3+-Catalyzed Cleavage of Dimethyl (o-Methoxycarbonyl)aryl Phosphate Triesters in Methanol

The catalytic methanolysis of a series of dimethyl aryl phosphate triesters where the aryl groups contain an o-methoxycarbonyl (o-CO2Me) substituent (4a-i) was studied at 25 degrees C in methanol containing La3+ at various concentrations and (s)(s)pH. Determination of the second-order rate constant for La3+(2)-catalyzed cleavage of substrate 4a (dimethyl (o-methoxycarbonyl)phenyl phosphate) as a function of (s)(s)pH was assessed in terms of a speciation diagram that showed that the process was catalyzed by La3+(2)(-OCH3)x dimers, where x = 1-5, that exhibit only a 5-fold difference in activity between all the species. The second-order catalytic rate constants (k2(La)) for the catalyzed methanolysis of 4a-i at (s)(s)pH 8.7 fit a Brønsted relationship of log k2(La) = (-0.82 +/- 0.11)(s)(s)pKa(lg) + (11.61 +/- 1.48), where the gradient is shallower than that determined for a series of dimethyl aryl phosphates that do not contain the o-CO2Me substituent, log k2(La) = (-1.25 +/- 0.06)(s)(s)pKa(lg) + (16.23 +/- 0.75). Two main observations are that (1) the o-CO2Me group preferentially accelerates the cleavage of the phosphate triesters with poor leaving groups relative to those with good leaving groups and (2) it provides an increase in cleavage rate relative to those of comparable substrates that do not have that functional group, e.g., k2(La)(dimethyl o-(methoxycarbonyl)phenyl phosphate)/k2(La)(dimethyl phenyl phosphate) = 60. Activation parameters for the La3+(2)-catalyzed methanolysis of 4a and dimethyl 4-nitrophenyl phosphate show respective DeltaH(double dagger) (DeltaS(double dagger)) values of 3.3 kcal/mol (-47 cal/mol x K) and 0.7 kcal/mol (-46.5 cal/mol x K). The data are analyzed in terms of a concerted reaction where the catalytic complex (La3+(2)(-OCH3)(x-1)) binds to the three components of a rather loose transition state composed of a nucleophile CH3O-, a nucleofuge -OAr, and a central (RO)2P(2+)-O(-) in a way that provides leaving group assistance to the departing aryloxy group.

Site-Selective, Copper-Mediated O-Arylation of Carbohydrate Derivatives

Site-selective functionalization of hydroxy groups in sugar derivatives is a major challenge in carbohydrate synthesis. Methods for achieving this goal will provide efficient access to new sugar-derived chemical building blocks and will facilitate the preparation or late-stage modification of complex oligosaccharides for applications in glycobiology research and drug discovery. Here, we describe site-selective, copper-promoted couplings of boronic acids with carbohydrate derivatives. These reactions generate sugar-derived aryl ethers, a structural class that is challenging to generate by other means and has not previously been accessed in a site-selective fashion. Experimental evidence and computational modeling suggest that the formation of a sugar-derived boronic ester intermediate is crucial to the selectivity of these processes, accelerating the arylation of an adjacent hydroxy group. The results demonstrate how the interactions of sugars with boron compounds can be combined with transition metal catalysis to achieve new chemical reactivity.

A Nonlinear Ordinary Differential Equation for Generating Graphical Rate Equations from Concentration Versus Time Data

When reaction progress kinetic analysis is implemented on data obtained using a spectroscopic or chromatographic technique such as ATR–FTIR, NMR, absorbance spectroscopy, HPLC or GC, an initial step involves fitting a mathematical function to the experimental concentration versus time data. This function is then differentiated to give graphs of rate versus substrate concentration (graphical rate equations). It is important that the function be able to accurately describe the experimental data without introducing bias or artifacts. Here, we put forward a nonlinear ordinary differential equation that can be fitted to experimental concentration versus time data for applications in reaction progress kinetic analysis. We show that it can be applied to data from catalytic transformations showing diverse types of kinetic behavior.

Mechanism of an Organoboron-Catalyzed Domino Reaction: Kinetic and Computational Studies of Borinic Acid-Catalyzed Regioselective Chloroacylation of 2,3-Epoxy Alcohols

A mechanistic study of the borinic acid-catalyzed chloroacylation of 2,3-epoxy alcohols is presented. In this unusual mode of catalysis, the borinic acid activates the substrate toward sequential reactions with a nucleophile (epoxide ring-opening by chloride) and an electrophile (O-acylation of the resulting alkoxide). Reaction progress kinetic analysis of data obtained through in situ FTIR spectroscopy is consistent with a mechanism involving turnover-limiting acylation of a chlorohydrin-derived borinic ester. This proposal is further supported by investigations of the effects of aroyl chloride substitution on reaction rate. The kinetics experiments also shed light on the effects of chloride concentration on reaction rate and indicate that the catalyst is subject to inhibition by the product of the chloroacylation reaction. Computational modeling is employed to gain insight into the effects of the organoboron catalyst on the regioselectivities of the epoxide ring-opening and acylation steps. The density functional theory calculations provide a plausible pathway for selective chlorinolysis at C-3 and benzoylation at O-1, as is observed experimentally.

Borinic Acid-Catalyzed, Regioselective Ring Opening of 3,4-Epoxy Alcohols

Diarylborinic acids (Ar2BOH) catalyze the C3-selective ring opening of 3,4-epoxy alcohols with aniline, dialkylamine and arenethiol nucleophiles. The regiochemical outcome is consistent with a catalytic tethering mechanism in which the borinic acid interacts with both the electrophile and the nucleophile. The rate acceleration resulting from this induced intramolecularity effect is sufficient to overcome steric biases that would otherwise favor C4-selective opening of the substituted epoxy alcohols.

Author Correction: Amine hemilability enables boron to mechanistically resemble either hydride or proton

During the revision of this Article prior to publication, a computational study was reported (Vallejos, M. M. & Pellegrinet, S. C. Theoretical study of the BF3-promoted rearrangement of oxiranyl N-methyliminodiacetic acid boronates. J. Org. Chem. 82, 5917–5925; 2017) that evaluates the nucleophilic boryl transfer mechanism predicted in this Article; this reference has now been added as number 19, and the subsequent references renumbered.

Amine hemilability enables boron to mechanistically resemble either hydride or proton

AbstractTetracoordinate MIDA (N-methyliminodiacetic acid) boronates have found broad utility in chemical synthesis. Here, we describe mechanistic insights into the migratory aptitude of the MIDA boryl group in boron transfer processes, and show that the hemilability of the nitrogen atom on the MIDA ligand enables boron to mechanistically resemble either a hydride or a proton. The first case involves a 1,2-boryl shift, in which boron migrates as a nucleophile in its tetracoordinate form. The second case involves a neighbouring atom-promoted 1,4-boryl shift, in which boron migrates as an electrophile in its pseudo-tricoordinate form. Density functional theory studies and in situ NMR measurements all suggest that MIDA can act as a dynamic switch. These findings encouraged the development of novel migration processes involving boron that exploit the chameleonic behaviour of boron by acting as both a nucleophile and an electrophile, including the first report of a compound with a boronate functionality bound to carbon in the carboxylic acid oxidation state.Mechanistic studies of the hemilability of MIDA (N-methyliminodiacetic acid) boronates reveal the chameleonic behaviour of the BMIDA group. The superior migratory aptitude of BMIDA compared to hydride and the capacity to resemble a proton when nitrogen decoordinates from boron have now been exploited for the design of new boron transfer reactions.