Kinetic isotope effects in complex reaction networks: formic acid electro-oxidation.

The determination of kinetic isotope effects (KIEs) for different reaction pathways and steps in a complex reaction network, where KIEs may affect the overall reaction in various different ways including dominant and minority pathways or the buildup of a reaction-inhibiting adlayer, is demonstrated for formic acid electrooxidation on a Pt film electrode by quantitative electrochemical in situ IR spectroscopic measurements under controlled mass-transport conditions. The ability to separate effects resulting from different contributions--which is not possible using purely electrochemical kinetic measurements--allows conclusions on the nature of the rate-limiting steps and their transition state in the individual reaction pathways. The potential-independent values of approximately 1.9 for the KIE of formic acid dehydration (CO(ad) formation) in the indirect pathway and approximately 3 for the CO(ad) coverage-normalized KIE of formic acid oxidation to CO2 (direct pathway) indicate that 1) C-H bond breaking is rate-limiting in both reaction steps, 2) the transition states for these reactions are different, and 3) the configurations of the transition states involve rather strong bonds to the transferred D/H species, either in the initial or in the final state, for the direct pathway and--even more pronounced--for formic acid dehydration (CO(ad) formation).     

Large concentration effects on the magnitude of secondary alpha-deuterium kinetic isotope effects

Because the secondary alpha-deuterium kinetic isotope effects in some S_N2 and E2 reactions are strongly concentration dependent, isotope effects measured at a single concentration could lead to erroneous conclusions about the mechanisms and transition state structures.     

Enantioselective organocatalytic Diels-Alder reactions: a density functional theory and kinetic isotope effects study

The mechanism and enantioselectivity of the organocatalytic Diels-Alder reaction were computationally investigated by density functional theory at the B3LYP/6-31G(d) level of theory. The uncatalyzed Diels-Alder reaction was also studied to explore the effect of the organocatalyst on this reaction in terms of energetics, selectivity, and mechanism. The catalyzed reaction showed improved endo/exo selectivity, and the free energy of activation was significantly lowered in the presence of the catalyst. Both uncatalyzed and catalyzed reactions exhibited concerted asynchronous reaction mechanism with the degree of asynchronicity being more evident in the presence of the catalyst. The Corey's experimentally derived predictive selection rules for the outcome of the organocatalytic Diels-Alder reaction were also theoretically analyzed, and an excellent agreement was found between experiment and theory.     

Mechanistic studies on the stereoselective formation of beta-mannosides from mannosyl iodides using alpha-deuterium kinetic isotope effects

Stereoselective synthesis of beta-mannosides is one of the most challenging linkages to achieve in carbohydrate chemistry. Both the anomeric effect and the C2 axial substituent favor the formation of the axial glycoside (alpha-product). Herein, we describe mechanistic studies on the beta-selective glycosidation of trimethylene oxide (TMO) using mannosyl iodides. Density functional calculations (at the B3LYP/6-31+G(d,p):LANL2DZ level) suggest that formation of both alpha- and beta-mannosides involve loose S(N)2-like transition-state structures with significant oxacarbenium character, although the transition structure for formation of the alpha-mannoside is significantly looser. alpha-Deuterium kinetic isotope effects (alpha-DKIEs) based upon these computed transition state geometries match reasonably well with the experimentally measured values: 1.16 +/- 0.02 for the beta-linkage (computed to be 1.15) and 1.19 +/- 0.05, see table 2 for the alpha-analogue (computed to be 1.26). Since it was unclear if beta-selectivity resulted from a conformational constraint induced by the anomeric iodide, a 4,6-O-benzylidine acetal was used to lock the iodide into a chairlike conformation. Both experiments and calculations on this analogue suggest that it does not mirror the behavior of mannosyl iodides lacking bridging acetal protecting groups.     

Electrophilic fluorination of aromatic compounds with NF type reagents: kinetic isotope effects and mechanism

H/D Isotope effects in fluorination of aromatic compounds with NF type reagents have been studied to reveal the reaction mechanism. The results obtained are consistent with a polar S_EAr mechanism. Small deuterium isotope effects (k_H/k_D = 0.86-0.99) show that decomposition of a Wheland-type intermediate is not rate determining. The first example of a 1,2-hydrogen shift accompanying electrophilic fluorination of arenes has been observed in the fluorination of 1,3,5-trideuterobenzene.     

Single-Step Glycosylations with 13C-Labelled Sulfoxide Donors: A Low-Temperature NMR Cartography of the Distinguishing Mechanistic Intermediates

Glycosyl sulfoxides have gained recognition in the total synthesis of complex oligosaccharides and as model substrates for dissecting the mechanisms involved. Reactions of these donors are usually performed under pre-activation conditions, but an experimentally more convenient single-step protocol has also been reported, whereby activation is performed in the presence of the acceptor alcohol; yet, the nature and prevalence of the reaction intermediates formed in this more complex scenario have comparatively received minimal attention. Herein, a systematic NMR-based study employing both ¹³C-labelled and unlabelled glycosyl sulfoxide donors for the detection and monitoring of marginally populated intermediates is reported. The results conclusively show that glycosyl triflates play a key role in these glycosylations despite the presence of the acceptor alcohol. Importantly, the formation of covalent donor/acceptor sulfonium adducts was identified as the main competing reaction, and thus a non-productive consumption of the acceptor that could limit the reaction yield was revealed.     

Secondary alpha-deuterium kinetic isotope effects: assumptions simplifying interpretations of mechanisms of solvolyses of secondary alkyl sulfonates

For solvolyses of 2-propyl and cyclopentyl sulfonates, logarithms of alpha-deuterium kinetic isotope effects (alpha-KIE) correlate linearly with logarithms of nucleophilic solvent assistance (NSA); correlations have the same slopes, but different intercepts, consistent with both solvent and structural effects on alpha-KIEs for heterolysis, further supported by recent theoretical and experimental data. It is argued that alpha- and beta-KIEs cannot yet distinguish between mechanisms proceeding via one or more transition states of similar energies. Structural, solvent, and isotope effects can be rationalized by heterolysis accompanied by NSA.     

Experimental and theoretical multiple kinetic isotope effects for an SN2 reaction. An attempt to determine transition-state structure and the ability of theoretical methods to predict experimental kinetic isotope effects

The secondary alpha-deuterium, the secondary beta-deuterium, the chlorine leaving-group, the nucleophile secondary nitrogen, the nucleophile (12)C/(13)C carbon, and the (11)C/(14)C alpha-carbon kinetic isotope effects (KIEs) and activation parameters have been measured for the S(N)2 reaction between tetrabutylammonium cyanide and ethyl chloride in DMSO at 30 degrees C. Then, thirty-nine readily available different theoretical methods, both including and excluding solvent, were used to calculate the structure of the transition state, the activation energy, and the kinetic isotope effects for the reaction. A comparison of the experimental and theoretical results by using semiempirical, ab initio, and density functional theory methods has shown that the density functional methods are most successful in calculating the experimental isotope effects. With two exceptions, including solvent in the calculation does not improve the fit with the experimental KIEs. Finally, none of the transition states and force constants obtained from the theoretical methods was able to predict all six of the KIEs found by experiment. Moreover, none of the calculated transition structures, which are all early and loose, agree with the late (product-like) transition-state structure suggested by interpreting the experimental KIEs.     

Mechanism of Remote Conjugate Addition of Lithium Organocuprates to Polyconjugated Carbonyl Compounds

Regioselective reaction of a lithium organocuprate (R₂CuLi) and a polyconjugated carbonyl compound affords a remote‐conjugate‐addition product. This reaction proceeds particularly cleanly when the conjugation is terminated by a C? C triple bond. The reaction pathways and the origin of the regioselectivity of this class of transformations are explored with the aid of density functional calculations. The outline of the reaction pathway is as follows. An initially formed β‐cuprio(III) enolate intermediate undergoes smooth copper migration along the conjugated system. This process takes place faster than reductive elimination of intermediary σ/π‐allylcopper(III) species, since the latter reaction disrupts the conjugation in the substrate and hence is not preferred. The copper migration to the acetylenic terminal affords a σ/π‐allenylcopper(III) intermediate, which undergoes facile and selective C? C bond forming reductive elimination at the terminal carbon atom. The present mechanistic framework shows good agreement with some pertinent experimental data, including ¹³C NMR chemical shifts and kinetic isotope effects.     

Ab initio path‐integral calculations of kinetic and equilibrium isotope effects on base‐catalyzed RNA transphosphorylation models

Detailed understandings of the reaction mechanisms of RNA catalysis in various environments can have profound importance for many applications, ranging from the design of new biotechnologies to the unraveling of the evolutionary origin of life. An integral step in the nucleolytic RNA catalysis is self‐cleavage of RNA strands by 2′‐O‐transphosphorylation. Key to elucidating a reaction mechanism is determining the molecular structure and bonding characteristics of transition state. A direct and powerful probe of transition state is measuring isotope effects on biochemical reactions, particularly if we can reproduce isotope effect values from quantum calculations. This article significantly extends the scope of our previous joint experimental and theoretical work in examining isotope effects on enzymatic and nonenzymatic 2′‐O‐transphosphorylation reaction models that mimic reactions catalyzed by RNA enzymes (ribozymes), and protein enzymes such as ribonuclease A (RNase A). Native reactions are studied, as well as reactions with thio substitutions representing chemical modifications often used in experiments to probe mechanism. Here, we report and compare results from eight levels of electronic‐structure calculations for constructing the potential energy surfaces in kinetic and equilibrium isotope effects (KIE and EIE) computations, including a “gold‐standard” coupled‐cluster level of theory [CCSD(T)]. In addition to the widely used Bigeleisen equation for estimating KIE and EIE values, internuclear anharmonicity and quantum tunneling effects were also computed using our recently developed ab initio path‐integral method, that is, automated integration‐free path‐integral method. The results of this work establish an important set of benchmarks that serve to guide calculations of KIE and EIE for RNA catalysis. © 2014 Wiley Periodicals, Inc.     

Vibrational analysis of a rate-slowing conformational kinetic isotope effect

An enthalpy-entropy approach to analyzing a rate-slowing conformational kinetic isotope effect (CKIE) in a deuterated doubly-bridged biaryl system is described. The computed isotope effect (k_H/k_D?=?1.075, 368?K) agrees well with the measured value (k_H/k_D?=?1.06, 368?K). The rate-slowing (normal isotope effect) nature of the computed CKIE is shown to originate from a vibrational entropy contribution defined by the twenty lowest frequency normal modes in the ground state and transition state structures. This normal entropy contribution is offset by an inverse vibrational enthalpy contribution, which also arises from the twenty lowest frequency normal modes. Zero point vibrational energy contributions are found to be relatively small when all normal modes are considered. Analysis of the H_ZPE, H_vib, and S_vib energy terms arising from the low frequency vibrational modes reveals their signs and magnitudes are determined by larger vibrational energy differences in the labeled and unlabeled ground state structures.     

Solvent-dependent changes in the triazolinedione-alkene ene reaction mechanism

The influence of the solvent on the triazolinedione-alkene ene reaction mechanism has been investigated. Both inter- and intramolecular kinetic isotope effects with tetramethylethylenes and 2,2,2-(trideuterio)methyl-7-methyl-2,6-octadiene-[D3]-1,1,1 provide, for the first time, strong evidence for changes in the mechanism of the reaction on going from non-protic to polar protic solvents. In non-protic polar or apolar solvents, an aziridinium imide that equilibrates to an insignificant extent with an open intermediate (a dipolar or a polarized biradical) is formed irreversibly in the first, rate-determining step of the reaction, which is followed by fast hydrogen abstraction. On the contrary, in polar protic solvents, hydrogen abstraction is rate limiting, allowing the main dipolar intermediate to equilibrate with its open intermediate(s) as well as with the starting reagents.