Mechanistic Studies Of The Halogen Effect In Sydnone Cycloadditions And The Selectivity In Carboboration Reactions

In recent years,bioorthogonal reactions have proven to be a powerful tool for cell labeling,disease diagnosis and drug releasing.With the development of bioorthogonal chemistry,a variety of bioorthogonal reagents are needed.Sydnone has the advantages of good stability,high biocompatibility and high reactivity which make it a new biorthogonal reagent.Various kinds of sydnones have been designed.Sydnone chemistry find its applications in biology,especially protein labeling,fluorescent turn-on probes and material synthesis.It has been reported that substituent effect on sydnone cycloaddition reactivity with strain alkyne is significant.However,it is not clear that how the substitute groups effect on the activity of sydnone.To understand how the substitute groups effect on the activity of sydnone,we will use DFT calculations to study the sydnone bioorthogonal cycloaddition reaction in this paper.With the advantage of theoretical calculation,we will study the selectivity of boron reagents in carboboration.Aromatic heterocyclic skeletons are widely found in natural products,pharmaceuticals,photoelectric materials.Motivated by developing efficient approaches to heteroatom-containing building blocks,a lot of research are carried out.At present,it is found that boron reagents can directly convert substrate to heteroatom-containing building blocks without catalysts.This kind of reaction has the advantages of low cost,high efficiency and simple procedure.However,the selectivity and reaction mechanism of boron reagents in the process of carboboration is not clear.We use DFT calculations to study the mechanism of carboboration.This paper is mainly talking about two parts in the following:In part one,we used DFT calculations to study the origins of halogen effects in bioorthogonal sydnone cycloadditions.We calculated the activation free energies and rate constants of sydnones cycloaddition reaction.Computational results are in good agreement with the experimentally measured rate constants.The calculated LUMO energies of sydnones are not well correlated with activation free energies,implying that substituents alter the cycloaddition reaction activity of sydnones through a more sophisticated mechanism.To better understand the halogen effects in sydnone cycloadditions,we used Distortion/Interaction Model to identify the origins of reactivity differences.The results show substituents mainly affect the distortion of sydnones to change the activity of cycloaddition.We calculated the enthalpy of hydrogenation reaction to evaluate the thermodynamic consequence how the halogen substituents effect on the sydnone nucleus.The results reveal the fact that stabilization prevents the distortion of sydnone toward its geometry in transition-state structure during cycloaddition.To compare directly how substituents alter the distortion energies of sydnones,we carried out a scan of out-of-plane distortion.The out-of-plane distortion converts an sp2C into an sp3C.The strongly electronegative F prefers to be attached to the sp3C hybridized carbon,which have more significant effects on lowering the out-of-plane distortion of sydnone.Our results reveal that halogen substitutes make sydnones easier to distort,decreasing the activation barrier substantially.The distortion-assisted acceleration in reactivity will inspire the future design of new biorthogonal reactions.We predicted the cycloaddition reaction rate of the parent sydnone and fluorosydnone,two disubstituted tetrazines,and methyl azide in reactions with 12 commonly used alkynes and alkenes in bioorthogonal chemistry.The predicted rate constant table makes it convenient to find mutually orthogonal cycloaddition pairs.In part two,we used DFT calculations to study the mechanism of carboboration.Take BCl3 and B-Chlorocatecholborane for example,we learned that boron reagents went through a concerted mechanism.Boron reagents activated alkyne at the time of nucleophilic group attacking the alkyne carbocation,then aromatic heterocyclic intermediates are formed.Finally,the target product can be obtained by demethylation.The approach that BCI3 convert ester in to acyl chloride lead to the selectivity in carboboration.We discover a new approach that BCI3 convert ester into acyl chloride.When BCI3 reacts with ester,the enhancement of electronic ability is beneficial to the reaction.And the reaction activity is insensitive to the steric effect.The rule is opposite to the classical ester hydrolysis process.It is found that the mechanism of reaction between BCl3 and ester is different from classical ester hydrolysis process.The reaction of BCl3 converts ester into acyl chloride will be useful in organic synthesis.This discovery provides a good complement to classical organic chemistry.And it inspires people to design new reactions.