Изотоп алмасу арқылы химиялық реакция жылдамдығының өзгеруі

Change in chemical reaction rate due to isotopic substitution

In physical organic chemistry, a kinetic isotope effect (KIE) is the change in the reaction rate of a chemical reaction when one of the atoms in the reactants is replaced by one of its isotopes. Depending on the pathway, different strategies may be used to stabilize the transition state of the rate determining step of the reaction and improve the reaction rate and selectivity, which are important for industrial applications. Isotopic rate changes are most pronounced when the relative mass change is greatest, since the effect is related to vibrational frequencies of the affected bonds. For instance, changing a hydrogen atom (H) to its isotope deuterium (D) represents a 100% increase in mass, whereas in replacing carbon 12 with carbon 13, the mass increases by only 8 percent. The rate of a reaction involving a C–H bond is typically 6–10 times faster than the corresponding C–D bond, whereas a 12C reaction is only 4 percent faster than the corresponding 13C reaction

In some cases, an additional rate enhancement is seen for the lighter isotope, possibly due to quantum mechanical tunnelling. This is typically only observed for reactions involving bonds to hydrogen atoms. Tunneling occurs when a molecule penetrates through a potential energy barrier rather than over it. Although not allowed by the laws of classical mechanics, particles can pass through classically forbidden regions of space in quantum mechanics based on wave–particle duality. In addition, the β term depends linearly with barrier width, 2a. As with mass, tunneling is greatest for small barrier widths. Optimal tunneling distances of protons between donor and acceptor atom is 0.4 Å.

Isotopic effect expressed with the equations given above only refer to reactions that can be described with first order kinetics. In all instances in which this is not possible, transient kinetic isotope effects should be taken into account using the GEBIK and GEBIF equations.

Kinetic isotope effect measurement at natural abundance is a simple general method for measuring kinetic isotope effects (KIE) for chemical reactions performed with materials of natural abundance. This technique for measuring KIEs overcomes many limitations of previous KIE measurement methods. KIE measurements from isotopically labeled materials require a new synthesis for each isotopically labeled material (a process often prohibitively difficult), a competition reaction, and an analysis. Singleton and coworkers demonstrated the capacity of C 13 NMR based natural abundance KIE measurements for studying the mechanism of the [4 + 2] cycloaddition of isoprene with maleic anhydride. This work by Singleton et al. established the measurement of multiple C 13 KIE's within the design of a single experiment. These H 2 and C 13 KIE measurements determined at natural abundance found the "inside" hydrogens of the diene experience a more pronounced H 2 KIE than the "outside" hydrogens" and the C1 and C4 experience a significant KIE. These key observations suggest an asynchronous reaction mechanism for the cycloaddition of isoprene with maleic anhydride. The limitations for determining KIE's at natural abundance using NMR are that the recovered material must have a suitable amount and purity for NMR analysis (the signal of interest should be distinct from other signals), the reaction of interest must be irreversible, and the reaction mechanism must not change for the duration of the chemical reaction. Experimental details for using quantitative single pulse NMR to measure kinetic isotope effect at natural abundance as follows: the experiment needs to be performed under quantitative conditions including a relaxation time of 5 T1, measured 90° flip angle, a digital resolution of at least 5 points across a peak, and a signal:noise greater than 250. The raw FID is zero filled to at least 256K points before the Fourier transform. NMR spectra are phased and then treated with a zeroth order baseline correction without any tilt correction. Signal integrations are determined numerically with a minimal tolerance for each integrated signal. The observation of a primary 13C isotope effect at C3, an inverse 2H isotope effect, a secondary 13C isotope effect at C2, and the lack of an 2H isotope effect at C2 lead Colletto et al. to suggest a Heck type reaction mechanism for the regioselective arylation of benzo[b]thiophenes at room temperature with aryl iodides as coupling partners. The primary 13C kinetic isotope effect observed in the absence of BPh3 suggests a reaction mechanism with rate limiting cis oxidation into the C–CN bond of the cyanoformamide. The addition of BPh3 causes a relative decrease in the observed 13C kinetic isotope effect which led Frost et al. to suggest a change in the rate limiting step from cis oxidation to coordination of palladium to the cyanoformamide. Jacobsen and coworkers identified the thiourea catalyzed glycosylation of galactose as a reaction that met both of the aforementioned criteria (expensive materials and unstable substrates) and was a reaction with a poorly understood mechanism. Glycosylation is a special case of nucleophilic substitution that lacks clear definition between SN1 and SN2 mechanistic character. The presence of the oxygen adjacent to the site of displacement (i. e., C1) can stabilize positive charge. This charge stabilization can cause any potential concerted pathway to become asynchronous and approaches intermediates with oxocarbenium character of the SN1 mechanism for glycosylation. Jacobsen and coworkers observed small normal KIE's at C1, C2, and C5 which suggests significant oxocarbenium character in the transition state and an asynchronous reaction mechanism with a large degree of charge separation.

High precision isotope ratio mass spectrometry (IRMS) is another method for measuring kinetic fractionation of isotopes for natural abundance KIE measurements. Widlanski and coworkers demonstrated S 34 KIE at natural abundance measurements for the hydrolysis of sulfate monoesters. Their observation of a large KIE suggests S O bond cleavage is rate controlling and likely rules out an associate reaction mechanism. The major limitation for determining KIE's at natural abundance using IRMS is the required site selective degradation without isotopic fractionation into an analyzable small molecule, a non trivial task. Such effects are expressed as ratios of rate for the light isotope to that of the heavy isotope and can be "normal" (ratio is greater than or equal to 1) or "inverse" (ratio is less than 1) effects. SKIE are defined as α,β (etc.) secondary isotope effects where such prefixes refer to the position of the isotopic substitution relative to the reaction center (see alpha and beta carbon). The prefix α refers to the isotope associated with the reaction center while the prefix β refers to the isotope associated with an atom neighboring the reaction center and so on. In physical organic chemistry, SKIE is discussed in terms of electronic effects such as induction, bond hybridization, or hyperconjugation. These properties are determined by electron distribution, and depend upon vibrationally averaged bond length and angles that are not greatly affected by isotopic substitution. Thus, the use of the term "electronic isotope effect" while legitimate is discouraged from use as it can be misinterpreted to suggest that the isotope effect is electronic in nature rather than vibrational. Path A involved a nucleophilic attack on the coenzyme FAD, while path B involves a free radical intermediate. As path A results in the intermediate carbon changing hybridization from sp2 to sp3 an "inverse" a SKIE is expected. If path B occurs then no SKIE should be observed as the free radical intermediate does not change hybridization. An SKIE of 0.84 was observed and Path A verified as shown in the scheme below. Another example of a SKIE is the oxidation of benzyl alcohols by dimethyldioxirane where three transition states for different mechanisms were proposed. Again, by considering how and if the hydrogen atoms were involved in each, researchers predicted whether or not they would expect an effect of isotopic substitution of them. Then, analysis of the experimental data for the reaction allowed them to choose which pathway was most likely based on the observed isotope effect. Secondary hydrogen isotope effects from the methylene hydrogens were also used to show that Cope rearrangement in 1,5 hexadiene follow a concerted bond rearrangement pathway, and not one of the alternatively proposed allyl radical or 1,4 diyl pathways, all of which are presented in the following scheme. Alternative mechanisms for the Cope rearrangement of 1,5 hexadiene: (from top to bottom), allyl radical, synchronous concerted, and 1,4 dyil pathways. The predominant pathway is found to be the middle one, which has six delocalized π electrons corresponding to an aromatic intermediate. An example of such an effect is the racemization of 9,10 dihydro 4,5 dimethylphenanthrene. The smaller amplitude of vibration for deuterium as compared to hydrogen in C–H (carbon–hydrogen), C–D (carbon–deuterium) bonds results in a smaller van der Waals radius or effective size in addition to a difference in the ZPE between the two. When there is a greater effective bulk of molecules containing one over the other this may be manifested by a steric effect on the rate constant. For the example above deuterium racemizes faster than the hydrogen isotopologue resulting in a steric isotope effect. A model for the steric isotope effect was developed by Bartell. A steric isotope effect is usually small, unless the transformations passes through a transition state with severe steric encumbrance, as in the racemization process shown above. Another example of the steric isotope effect is in the deslipping reaction of rotaxanes. The deuterium isotope, due to its smaller effective size, allows easier passage of the stoppers through the macrocycle, resulting in faster rates of deslipping for the deuterated rotaxanes.