Modeling the Reaction of Carboxylic Acids and Isonitriles in a Self‐Assembled Capsule

Quantum chemical calculations were used to study the reaction of carboxylic acids with isonitriles inside a resorcinarene‐based self‐assembled capsule. Experimentally, it has been shown that the reactions between p‐tolylacetic acid and n‐butyl isonitrile or isopropyl isonitrile behave differently in the presence of the capsule compared both with each other and also with their solution counterparts. Herein, the reasons for these divergent behaviors are addressed by comparing the detailed energy profiles for the reactions of the two isonitriles inside and outside the capsule. An energy decomposition analysis was conducted to quantify the different factors affecting the reactivity. The calculations reproduce the experimental findings very well. Thus, encapsulation leads to lowering of the energy barrier for the first step of the reaction, the concerted α‐addition and proton transfer, which in solution is rate‐determining, and this explains the rate acceleration observed in the presence of the capsule. The barrier for the final step of the reaction, the 1,3 O→N acyl transfer, is calculated to be higher with the isopropyl substituent inside the capsule compared with n‐butyl. With the isopropyl substituent, the transition state and the product of this step are significantly shorter than the preceding intermediate, and this results in energetically unfavorable empty spaces inside the capsule, which cause a higher barrier. With the n‐butyl substituent, on the other hand, the carbon chain can untwine and hence uphold an appropriate guest length.