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Labelling and determination of the energy in reactive intermediates in solution enabled by energy-dependent reaction selectivity.

ABSTRACT: Any long-lived chemical structure in solution is subject to statistical energy equilibration, so the history of any specific structure does not affect its subsequent reactions. This is not true for very short-lived intermediates because energy equilibration takes time. Here, this idea is applied to achieve the 'energy labelling' of a reactive intermediate. The selectivity of the ring-opening ?-cleavage reaction of the 1-methylcyclobutoxy radical is found here to vary broadly depending on how the radical was formed. Reactions that provide little excess energy to the intermediate lead to a high selectivity in the subsequent cleavage (measured as a kinetic isotope effect), whereas reactions that provide more excess energy to the intermediate exhibit a lower selectivity. Accounting for the expected excess energy allows the prediction of the observed product ratios and, in turn, the product ratios can be used to determine the energy present in an intermediate.

SUBMITTER: Kurouchi H

PROVIDER: S-EPMC5785089 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Labelling and determination of the energy in reactive intermediates in solution enabled by energy-dependent reaction selectivity.

Kurouchi Hiroaki H Singleton Daniel A DA

Nature chemistry 20180101 2

Any long-lived chemical structure in solution is subject to statistical energy equilibration, so the history of any specific structure does not affect its subsequent reactions. This is not true for very short-lived intermediates because energy equilibration takes time. Here, this idea is applied to achieve the 'energy labelling' of a reactive intermediate. The selectivity of the ring-opening α-cleavage reaction of the 1-methylcyclobutoxy radical is found here to vary broadly depending on how the ...[more]

PMID: 29359761

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Project description:Determining the accurate chemical structures of synthesized compounds is essential for biomedical studies and computer-assisted drug design. The unequivocal determination of N-adamantylation or N-arylation site(s) in nitrogen-rich heterocycles, characterized by a low density of hydrogen atoms, using NMR methods at natural isotopic abundance is difficult. In these compounds, the heterocyclic moiety is covalently attached to the carbon atom of the substituent group that has no bound hydrogen atoms, and the connection between the two moieties of the compound cannot always be established via conventional 1H-1H and 1H-13C NMR correlation experiments (COSY and HMBC, respectively) or nuclear Overhauser effect spectroscopy (NOESY or ROESY). The selective incorporation of 15N-labelled atoms in different positions of the heterocyclic core allowed for the use of 1H-15N (JHN) and 13C-15N (JCN) coupling constants for the structure determinations of N-alkylated nitrogen-containing heterocycles in solution. This method was tested on the N-adamantylated products in a series of azolo-1,2,4-triazines and 1,2,4-triazolo[1,5-a]pyrimidine. The syntheses of adamantylated azolo-azines were based on the interactions of azolo-azines and 1-adamatanol in TFA solution. For azolo-1,2,4-triazinones, the formation of mixtures of N-adamantyl derivatives was observed. The JHN and JCN values were measured using amplitude-modulated 1D 1H spin-echo experiments with the selective inversion of the 15N nuclei and line-shape analysis in the 1D 13С spectra acquired with selective 15N decoupling, respectively. Additional spin-spin interactions were detected in the 15N-HMBC spectra. NMR data and DFT (density functional theory) calculations permitted to suggest a possible mechanism of isomerization for the adamantylated products of the azolo-1,2,4-triazines. The combined analysis of the JHN and JCN couplings in 15N-labelled compounds provides an efficient method for the structure determination of N-alkylated azolo-azines even in the case of isomer formation. The isomerization of adamantylated tetrazolo[1,5-b][1,2,4]triazin-7-ones in acidic conditions occurs through the formation of the adamantyl cation.

Dataset Information

Labelling and determination of the energy in reactive intermediates in solution enabled by energy-dependent reaction selectivity.

Publications

Labelling and determination of the energy in reactive intermediates in solution enabled by energy-dependent reaction selectivity.

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